Question: what drugs have been active against SARS-CoV or SARS-CoV-2 in animal studies?

Title: Search for SARS-CoV-2 inhibitors in currently approved drugs to tackle COVID-19 pandemia Content: Different treatments are currently used for clinical management of SARS-CoV-2 infection, but little is known about their efficacy yet. Here we present ongoing results to compare currently available drugs for a variety of diseases to find out if they counteract SARS-CoV-2-induced cytopathic effect in vitro. Our goal is to prioritize antiviral activity to provide a solid evidence-driven rationale for forthcoming clinical trials. Since the most effective antiviral approaches are usually based on combined therapies that tackle the viral life cycle at different stages, we are also testing combinations of drugs that may be critical to reduce the emergence of resistant viruses. We will provide results as soon as they become available, so data should be interpreted with caution, clearly understanding the limitations of the in vitro model, that may not always reflect what could happen in vivo. Thus, our goal is to test the most active antivirals identified in adequate animal models infected with SARS-CoV-2, to add more information about possible in vivo efficacy. In turn, successful antivirals could be tested in clinical trials as treatments for infected patients, but also as pre-exposure prophylaxis to avoid novel infections until an effective and safe vaccine is developed.

Title: Antiviral treatment of SARS-CoV-2-infected hamsters reveals a weak effect of favipiravir and a complete lack of effect for hydroxychloroquine Content: SARS-CoV-2 rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus was able to infect millions of people. To date, close to half a million patients succumbed to the viral disease, COVID-19. The high need for treatment options, together with the lack of small animal models of infection has led to clinical trials with repurposed drugs before any preclinical in vivo evidence attesting their efficacy was available. We used Syrian hamsters to establish a model to evaluate antiviral activity of small molecules in both an infection and a transmission setting. Upon intranasal infection, the animals developed high titers of SARS-CoV-2 in the lungs and pathology similar to that observed in mild COVID-19 patients. Treatment of SARS-CoV-2-infected hamsters with favipiravir or hydroxychloroquine (with and without azithromycin) resulted in respectively a mild or no reduction in viral RNA and infectious virus. Micro-CT scan analysis of the lungs showed no improvement compared to non-treated animals, which was confirmed by histopathology. In addition, both compounds did not prevent virus transmission through direct contact and thus failed as prophylactic treatments. By modelling the PK profile of hydroxychloroquine based on the trough plasma concentrations, we show that the total lung exposure to the drug was not the limiting factor. In conclusion, we here characterized a hamster infection and transmission model to be a robust model for studying in vivo efficacy of antiviral compounds. The information acquired using hydroxychloroquine and favipiravir in this model is of critical value to those designing (current and) future clinical trials. At this point, the data here presented on hydroxychloroquine either alone or combined with azithromycin (together with previously reported in vivo data in macaques and ferrets) provide no scientific basis for further use of the drug in humans.

Title: Medication for COVID-19—an Overview of Approaches Currently Under Study Content: BACKGROUND: With the worldwide spread of SARS-CoV-2 infection, it is becoming increasingly urgent to develop a vaccine to prevent COVID-19, as well as effective drugs to treat it. METHODS: This article is based on a selective literature search in PubMed and ClinicalTrials.gov, followed by an assessment of the ongoing clinical trials that were revealed by the search. RESULTS: A number of substances have been found to prevent the reproduction of SARS-CoV-2 in vitro. These include virustatic agents that have already been approved for the treatment of other types of viral infection, as well as drugs that are currently used for entirely different purposes. High in vitro activity has been found for the nucleotide analogue remdesivir, for the antimalarial drug chloroquine, and for nitazoxanide, a drug used to treat protozoan infections. Because the virus enters human cells by way of the membrane-associated angiotensin converting enzyme 2 (ACE2), keeping the virus from docking to this receptor is a conceivable treatment approach. Transmembrane protease serine 2 (TMPRSS2) plays a role in the fusion of the virus with cells; inhibitors of this enzyme are known as well. The potential therapeutic efficacy and tolerability of these and other active substances remain to be investigated in clinical trials. At present, more than 80 trials on COVID-10 have already been registered with ClinicalTrials.gov. Some initial findings should already be available in late April 2020. CONCLUSION: Clinical trials are now indispensable in order to determine the true clinical benefits and risks of the substances that have been found to be active against SARS-CoV-2 in vitro. There is not yet any recommendation for the therapeutic use of any particular agent beyond standard supportive treatment.

Title: Medication for COVID-19-an Overview of Approaches Currently Under Study Content: BACKGROUND: With the worldwide spread of SARS-CoV-2 infection, it is becoming increasingly urgent to develop a vaccine to prevent COVID-19, as well as effective drugs to treat it. METHODS: This article is based on a selective literature search in PubMed and ClinicalTrials.gov, followed by an assessment of the ongoing clinical trials that were revealed by the search. RESULTS: A number of substances have been found to prevent the reproduction of SARS-CoV-2 in vitro. These include virustatic agents that have already been approved for the treatment of other types of viral infection, as well as drugs that are currently used for entirely different purposes. High in vitro activity has been found for the nucleotide analogue remdesivir, for the antimalarial drug chloroquine, and for nitazoxanide, a drug used to treat protozoan infections. Because the virus enters human cells by way of the membrane-associated angiotensin converting enzyme 2 (ACE2), keeping the virus from docking to this receptor is a conceivable treatment approach. Transmembrane protease serine 2 (TMPRSS2) plays a role in the fusion of the virus with cells; inhibitors of this enzyme are known as well. The potential therapeutic efficacy and tolerability of these and other active substances remain to be investigated in clinical trials. At present, more than 80 trials on COVID-10 have already been registered with Clinical- Trials.gov. Some initial findings should already be available in late April 2020. CONCLUSION: Clinical trials are now indispensable in order to determine the true clinical benefits and risks of the substances that have been found to be active against SARSCoV- 2 in vitro. There is not yet any recommendation for the therapeutic use of any particular agent beyond standard supportive treatment.

Title: Remdesivir potently inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice Content: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 as the causative agent of the novel pandemic viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for safe, broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV), a monophosphoramidate prodrug of an adenosine analog, potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM). Weaker activity was observed in Vero E6 cells (EC50 = 1.65 μM) due to their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase, of SARS-CoV-2. In mice infected with chimeric virus, therapeutic RDV administration diminished lung viral load and improved pulmonary function as compared to vehicle treated animals. These data provide evidence that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19.

Title: Drug repurposing clinical trials in the search for life-saving COVID-19 therapies;research targets and methodological and ethical issues Content: Introduction: So far, there is no vaccine, nor are there effective drugs to treat COVID-19, an emerging viral respiratory infection deadlier than influenza Objective: To take a snapshot picture of planned and ongoing clinical research addressing drugs potentially useful for treating SAR-CoV-2 infections Method: A search was conducted (20 April 2020) in an international registry of clinical studies (https://ClinicalTrials gov, US NIH) After excluding observational studies and other interventions that fell outside the scope of this study, 294 research protocols (out of 516 retrieved protocols) were selected for analysis Results: Of 294 included trials, 249 were Randomized Controlled Trials (RCT), 118 of which were double-, triple- or quadruple-blinded studies The interventions (drug therapies) were compared with "standard-of-care" (SOC) or with the placebo plus SOC, or yet with presumed "active" comparators RCT focused on the primary treatment of the disease (inhibitors of viral replication) or on the therapy for resolution of hyperinflammation in pneumonia/Acute Respiratory Distress Syndrome (ARDS) and thromboembolism associated with SARS-CoV-2 The trials found in the database involve existing antiviral compounds and drugs with multiple modes of antiviral action Antiparasitic drugs, which inhibited viral replication in cell-culture assays, are being tested as well Regarding the adjunctive immunomodulatory, anti-inflammatory and antithrombotic therapies, a number of drugs with distinct pharmacological targets are under investigation in trials enrolling patients with severe COVID-19 Conclusions: Although many clinical studies of drugs for COVID-19 are planned or in progress, only a minority of them are sufficiently large, randomized and placebo-controlled trials with masking and concealment of allocation Owing to methodological limitations, only a few clinical trials found in the registry are likely to yield robust evidence of effectiveness and safety of drugs repurposable for COVID-19

Title: Development of remdesivir repositioning as a nucleotide analog against COVID-19 RNA dependent RNA polymerase Content: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative representative of a severe respiratory illness resulted in widespread human infections and deaths in nearly all of the countries since late 2019. There is no therapeutic FDA-approved drug against SARS-CoV-2 infection, although a combination of anti-viral drugs is directly being practiced in some countries. A broad-spectrum of antiviral agents are being currently evaluated in clinical trials, and in this review, we specifically focus on the application of Remdesivir (RVD) as a potential anti-viral compound against Middle East respiratory syndrome (MERS) -CoV, SARS-CoV and SARS-CoV-2. First, we overview the general information about SARS-CoV-2, followed by application of RDV as a nucleotide analogue which can potentially inhibits RNA-dependent RNA polymerase of COVs. Afterwards, we discussed the kinetics of SARS- or MERS-CoV proliferation in animal models which is significantly different compared to that in humans. Finally, some ongoing challenges and future perspective on the application of RDV either alone or in combination with other anti-viral agents against CoVs infection were surveyed to determine the efficiency of RDV in preclinical trials. As a result, this paper provides crucial evidence of the potency of RDV to prevent SARS-CoV-2 infections.Communicated by Ramaswamy H. Sarma.

Title: Development of remdesivir repositioning as a nucleotide analog against COVID-19 RNA dependent RNA polymerase Content: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative representative of a severe respiratory illness resulted in widespread human infections and deaths in nearly all of the countries since late 2019. There is no therapeutic FDA-approved drug against SARS-CoV-2 infection, although a combination of anti-viral drugs is directly being practiced in some countries. A broad-spectrum of antiviral agents are being currently evaluated in clinical trials, and in this review, we specifically focus on the application of Remdesivir (RVD) as a potential anti-viral compound against Middle East respiratory syndrome (MERS) -CoV, SARS-CoV and SARS-CoV-2. First, we overview the general information about SARS-CoV-2, followed by application of RDV as a nucleotide analogue which can potentially inhibits RNA-dependent RNA polymerase of COVs. Afterwards, we discussed the kinetics of SARS- or MERS-CoV proliferation in animal models which is significantly different compared to that in humans. Finally, some ongoing challenges and future perspective on the application of RDV either alone or in combination with other anti-viral agents against CoVs infection were surveyed to determine the efficiency of RDV in preclinical trials. As a result, this paper provides crucial evidence of the potency of RDV to prevent SARS-CoV-2 infections. Communicated by Ramaswamy H. Sarma

Title: Broad anti-coronaviral activity of FDA approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo Content: SARS-CoV-2 emerged in China at the end of 2019 and has rapidly become a pandemic with roughly 2.7 million recorded COVID-19 cases and greater than 189,000 recorded deaths by April 23rd, 2020 (www.WHO.org). There are no FDA approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA approved drugs. Rapid development and human testing of potential antivirals is greatly needed. A quick way to test compounds with potential antiviral activity is through drug repurposing. Numerous drugs are already approved for human use and subsequently there is a good understanding of their safety profiles and potential side effects, making them easier to fast-track to clinical studies in COVID-19 patients. Here, we present data on the antiviral activity of 20 FDA approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV. We found that 17 of these inhibit SARS-CoV-2 at a range of IC50 values at non-cytotoxic concentrations. We directly follow up with seven of these to demonstrate all are capable of inhibiting infectious SARS-CoV-2 production. Moreover, we have evaluated two of these, chloroquine and chlorpromazine, in vivo using a mouse-adapted SARS-CoV model and found both drugs protect mice from clinical disease.

Title: SARS CoV-2: Recent Reports on Antiviral Therapies Based on Lopinavir/Ritonavir, Darunavir/Umifenovir, Hydroxychloroquine, Remdesivir, Favipiravir and Other Drugs for the Treatment of the New Coronavirus. Content: Here we report on the most recent updates on experimental drugs successfully employed in the treatment of the disease caused by SARS CoV-2 coronavirus, also referred to as COVID-19 (COronaVIrus Disease 19). In particular, several cases of recovered patients have been reported after being treated with lopinavir/ritonavir (which is widely used to treat human immunodeficiency virus (HIV) infection) in combination with the anti-flu drug oseltamivir. In addition, remdesivir, which has been previously administered to Ebola virus patients, has also proven effective in the U.S. against coronavirus, while antimalarial chloroquine and hydroxychloroquine, favipiravir and co-administered darunavir and umifenovir (in patient therapies) were also recently recorded as having anti-SARS CoV-2 effects. Since the recoveries/deaths ratio in the last weeks significantly increased, especially in China, it is clear that the experimental antiviral therapy, together with the availability of intensive care unit beds in hospitals and rigorous government control measures, all play an important role in dealing with this virus. This also stresses the urgent need for the scientific community to devote its efforts to find other more specific antiviral strategies.

Title: Development of antiviral therapy for severe acute respiratory syndrome Content: Abstract A new disease, the severe acute respiratory distress syndrome (SARS), caused by the SARS coronavirus (SARS-CoV), emerged at the beginning of 2003 and rapidly spread throughout the world. Although the disease had disappeared in June 2003 its re-emergence cannot be excluded. The development of vaccines against SARS-CoV may take years. Therefore, the availability of effective antiviral drugs against SARS-CoV may be crucial for the control of future SARS outbreaks. In this review, experimental and clinical data about potential anti-SARS drugs is summarised and discussed. Animal model studies will be needed to help to determine which interventions warrant controlled clinical testing.

Title: Current pharmacological treatments for SARS-COV-2: A narrative review Content: The novel coronavirus, later identified as SARS-CoV-2, originating from Wuhan in China in November 2019, quickly spread around the world becoming a pandemic. Despite the knowledge of previous coronaviruses, such as those responsible for the SARS and MERS-CoV epidemic, there is no drug or prophylaxis treatment to this day. The rapid succession of scientific findings on SARS-CoV-2 provides a significant number of potential drug targets. Nevertheless, at the same time, the high quantity of clinical data, generated by a large number of rapidly infected people, require accurate tests regarding effective medical treatments. Several in vitro and in vivo studies were rapidly initiated after the outbreak of the pandemic COVID-19. Initial clinical studies revealed the promising potential of remdesivir that demonstrated a powerful and specific in vitro antiviral activity for COVID-19. Promising effects appear to be attributable to hydroxychloroquine. Remdesivir and hydroxychloroquine are being tested in ongoing randomized trials. In contrast, oseltamivir was not effective and corticosteroids are not currently recommended. However, few data from ongoing clinical trials are identifying low molecular weight heparins, innate immune system stimulating agents, and inflammatory modulating agents as potential effective agents. The authors assume that the current pandemic will determine the need for a systematic approach based on big data analysis for identifying effective drugs to defeat SARS-Cov-2. This work is aimed to be a general reference point and to provide an overview as comprehensive as possible regarding the main clinical trials in progress at the moment.

Title: In vitro data of current therapies for SARS-CoV-2. Content: BACKGROUND In December 2019, a new coronavirus, named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has emerged from China causing pneumonia outbreaks first in the Wuhan region and currently worldwide. In the light of the lack of efficient and specific treatments and the need to contain the epidemic, drug repurposing appears to be the most efficient tool to find therapeutic solution. OBJECTIVES The aim of this study was to summarize in vitro data of current agents used for the management of SARSCoV-2 all over the world. METHODS A literature search of articles from January 2000 until April 2020 was performed using MEDLINE, EMBASE and the Cochrane Library to assess in vitro data of current or putative therapies for SARS-CoV-2. RESULTS Although in vitro studies are scarce, data regarding chloroquine and hydroxychloroquine, remdesivir, nitazoxanide, teicoplanin, ivermectin, lopinavir, homoharringtonine and emetine seem promising. CONCLUSION Scientist all over the world should work together and increase their efforts in order to find feasible and efficient solutions against this new global viral threat.

Title: A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV-2 main protease Content: The SARS coronavirus type 2 (SARS-CoV-2) emerged in late 2019 as a zoonotic virus highly transmissible between humans that has caused the COVID-19 pandemic 1,2. This pandemic has the potential to disrupt healthcare globally and has already caused high levels of mortality, especially amongst the elderly. The overall case fatality rate for COVID-19 is estimated to be ∼2.3% overall 3 and 32.3% in hospitalized patients age 70-79 years 4. Therapeutic options for treating the underlying viremia in COVID-19 are presently limited by a lack of effective SARS-CoV-2 antiviral drugs, although steroidal anti-inflammatory treatment can be helpful. A variety of potential antiviral targets for SARS-CoV-2 have been considered including the spike protein and replicase. Based upon previous successful antiviral drug development for HIV-1 and hepatitis C, the SARS-CoV-2 main protease (Mpro) appears an attractive target for drug development. Here we show the existing pharmacopeia contains many drugs with potential for therapeutic repurposing as selective and potent inhibitors of SARS-CoV-2 Mpro. We screened a collection of ∼6,070 drugs with a previous history of use in humans for compounds that inhibit the activity of Mpro in vitro. In our primary screen we found ∼50 compounds with activity against Mpro (overall hit rate <0.75%). Subsequent dose validation studies demonstrated 8 dose responsive hits with an IC50 ≤ 50 μM. Hits from our screen are enriched with hepatitis C NS3/4A protease targeting drugs including Boceprevir (IC50=0.95 μM), Ciluprevir (20.77μM). Narlaprevir (IC50=1.10μM), and Telaprevir (15.25μM). These results demonstrate that some existing approved drugs can inhibit SARS-CoV-2 Mpro and that screen saturation of all approved drugs is both feasible and warranted. Taken together this work suggests previous large-scale commercial drug development initiatives targeting hepatitis C NS3/4A viral protease should be revisited because some previous lead compounds may be more potent against SARS-CoV-2 Mpro than Boceprevir and suitable for rapid repurposing.

Title: Remdesivir inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice. Content: Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the novel viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV) potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM). Weaker activity is observed in Vero E6 cells (EC50 = 1.65 μM) due to their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase, of SARS-CoV-2. In mice infected with chimeric virus, therapeutic RDV administration diminishes lung viral load and improves pulmonary function compared to vehicle treated animals. These data demonstrate that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19.

Title: Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Content: Effective therapeutics to treat COVID-19 are urgently needed. While many investigational, approved, and repurposed drugs have been suggested, preclinical data from animal models can guide the search for effective treatments by ruling out treatments without in vivo efficacy. Remdesivir (GS-5734) is a nucleotide analog prodrug with broad antiviral activity1,2, that is currently investigated in COVID-19 clinical trials and recently received Emergency Use Authorization from the US Food and Drug Administration3,4. In animal models, remdesivir treatment was effective against MERS-CoV and SARS-CoV infection.2,5,6 In vitro, remdesivir inhibited replication of SARS-CoV-2.7,8 Here, we investigated the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection9. In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs and reduced virus titers in bronchoalveolar lavages 12hrs after the first treatment administration. Virus shedding from the upper respiratory tract was not reduced by remdesivir treatment. At necropsy, lung viral loads of remdesivir-treated animals were lower and there was a reduction in damage to the lungs. Thus, therapeutic remdesivir treatment initiated early during infection had a clinical benefit in SARS-CoV-2-infected rhesus macaques. Although the rhesus macaque model does not represent the severe disease observed in a proportion of COVID-19 patients, our data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to pneumonia.

Title: Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2 Content: Effective therapeutics to treat COVID-19 are urgently needed. While many investigational, approved, and repurposed drugs have been suggested, preclinical data from animal models can guide the search for effective treatments by ruling out treatments without in vivo efficacy. Remdesivir (GS-5734) is a nucleotide analog prodrug with broad antiviral activity1,2, that is currently investigated in COVID-19 clinical trials and recently received Emergency Use Authorization from the US Food and Drug Administration3,4. In animal models, remdesivir treatment was effective against MERS-CoV and SARS-CoV infection.2,5,6 In vitro, remdesivir inhibited replication of SARS-CoV-2.7,8 Here, we investigated the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection9. In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs and reduced virus titers in bronchoalveolar lavages 12hrs after the first treatment administration. Virus shedding from the upper respiratory tract was not reduced by remdesivir treatment. At necropsy, lung viral loads of remdesivir-treated animals were lower and there was a reduction in damage to the lungs. Thus, therapeutic remdesivir treatment initiated early during infection had a clinical benefit in SARS-CoV-2-infected rhesus macaques. Although the rhesus macaque model does not represent the severe disease observed in a proportion of COVID-19 patients, our data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to pneumonia.

Title: In vitro data of current therapies for SARS-CoV-2 Content: BACKGROUND: In December 2019, a new coronavirus, named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has emerged from China causing pneumonia outbreaks first in the Wuhan region and currently worldwide. In the light of the lack of efficient and specific treatments and the need to contain the epidemic, drug repurposing appears to be the most efficient tool to find therapeutic solution. OBJECTIVES: The aim of this study was to summarize in vitro data of current agents used for the management of SARSCoV-2 all over the world. METHODS: A literature search of articles from January 2000 until April 2020 was performed using MEDLINE, EMBASE and the Cochrane Library to assess in vitro data of current or putative therapies for SARS-CoV-2. RESULTS: Although in vitro studies are scarce, data regarding chloroquine and hydroxychloroquine, remdesivir, nitazoxanide, teicoplanin, ivermectin, lopinavir, homoharringtonine and emetine seem promising. CONCLUSION: Scientist all over the world should work together and increase their efforts in order to find feasible and efficient solutions against this new global viral threat.

Title: Dermatological therapies with relevance to COVID-19 Content: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel single-stranded RNA virus that has gripped humanity all over. It affects primarily the respiratory system, but is not limited to it, causing widespread involvement of many organ systems. The cases are still rising at an exponential rate and manifold trials are on to test different agents with the hope for potential limitation of spread and control of symptoms. Various classes of drugs have been tried; some with moderate success while many are yet to be proven to be of definite benefit. We have observed that the drugs used in dermatology practice are featured in more than a few of such studies. Here, we wish to highlight the ones that we are familiar with, which has featured at some point, in the management of this very challenging pandemic.

Title: Protection from infection with severe acute respiratory syndrome coronavirus in a Chinese hamster model by equine neutralizing F(ab')2. Content: To warrant potential clinical testing, the equine anti-severe acute respiratory syndrome coronavirus (SARS-CoV) F(ab')(2) requires evaluation in as many animal models as possible. In this study, we established a new animal model, the Chinese hamster, susceptible to SARS-CoV infection. SARS-CoV could propagate effectively and sustain high levels for 1 wk in animal lungs. All animals were protected from SARS-CoV infection in preventive settings. Further, when used therapeutically this antibody led to an approximately 4-log(10) decrease in viral burden in infected animal lungs. The pathological changes in lungs correlated closely with the dose of antibody administered. The excellent preventive and therapeutic roles of equine anti-SARS-CoV F(ab')(2) in several animal models, including the novel Chinese hamster model described in this study, have provided exciting data concerning its potential clinical study.

Title: The challenging pathway towards the identification of SARS-CoV-2/COVID-19 therapeutics Content: The development of therapeutic agents against SARS-CoV-2/COVID-19 faces numerous barriers and a multidisciplinary approach to evaluating drug efficacy and toxicity is essential. Experimental and preclinical data should be integrated into a comprehensive analysis, where drug potency, the timing of therapy initiation, drug combinations, variability in systemic and local drug exposure and short- and long-term toxicities represent fundamental factors for the rational identification of candidates and prioritization of clinical investigations. Although the identification of SARS-CoV-2 therapeutics is a priority, rigorous and transparent methodologies are crucial to ensure that accelerated research programmes result in high-quality and reproducible findings.

Title: Small molecules targeting severe acute respiratory syndrome human coronavirus. Content: Severe acute respiratory syndrome (SARS) is an infectious disease caused by a novel human coronavirus. Currently, no effective antiviral agents exist against this type of virus. A cell-based assay, with SARS virus and Vero E6 cells, was developed to screen existing drugs, natural products, and synthetic compounds to identify effective anti-SARS agents. Of >10,000 agents tested, approximately 50 compounds were found active at 10 microM; among these compounds, two are existing drugs (Reserpine 13 and Aescin 5) and several are in clinical development. These 50 active compounds were tested again, and compounds 2-6, 10, and 13 showed active at 3 microM. The 50% inhibitory concentrations for the inhibition of viral replication (EC(50)) and host growth (CC(50)) were then measured and the selectivity index (SI = CC(50)/EC(50)) was determined. The EC(50), based on ELISA, and SI for Reserpine, Aescim, and Valinomycin are 3.4 microM (SI = 7.3), 6.0 microM (SI = 2.5), and 0.85 microM (SI = 80), respectively. Additional studies were carried out to further understand the mode of action of some active compounds, including ELISA, Western blot analysis, immunofluorescence and flow cytometry assays, and inhibition against the 3CL protease and viral entry. Of particular interest are the two anti-HIV agents, one as an entry blocker and the other as a 3CL protease inhibitor (K(i) = 0.6 microM).

Title: Antiviral drug discovery against SARS-CoV. Content: Severe Acute Respiratory Syndrome (SARS) is a life-threatening infectious disease caused by SARS-CoV. In the 2003 outbreak, it infected more than 8,000 people worldwide and claimed the lives of more than 900 victims. The high mortality rate resulted, at least in part, from the absence of definitive treatment protocols or therapeutic agents. Although the virus spreading has been contained, due preparedness and planning, including the successful development of antiviral drugs against SARS-CoV, is necessary for possible reappearance of SARS. In this review, we have discussed currently available strategies for antiviral drug discovery and how these technologies have been utilized to identify potential antiviral agents for the inhibition of SARS-CoV replication. Moreover, progress in the drug development based on different molecular targets is also summarized, including 1) Compounds that block the S protein-ACE2-mediated viral entry; 2) Compounds targeting SARS-CoV M(pro); 3) Compounds targeting papain-like protease 2 (PLP2); 4) Compounds targeting SARS-CoV RdRp; 5) Compounds targeting SARS-CoV helicase; 6) Active compounds with unspecified targets; and 7) Research on siRNA. This review aims to provide a comprehensive account of drug discovery on SARS. The experiences with the SARS outbreak and drug discovery would certainly be an important lesson for the drug development for any new viral outbreaks that may emerge in the future.

Title: SARS-CoV-2: Repurposed Drugs and Novel Therapeutic Approaches-Insights into Chemical Structure-Biological Activity and Toxicological Screening Content: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic represents the primary public health concern nowadays, and great efforts are made worldwide for efficient management of this crisis Considerable scientific progress was recorded regarding SARS-CoV-2 infection in terms of genomic structure, diagnostic tools, viral transmission, mechanism of viral infection, symptomatology, clinical impact, and complications, but these data evolve constantly Up to date, neither an effective vaccine nor SARS-CoV-2 specific antiviral agents have been approved, but significant advances were enlisted in this direction by investigating repurposed approved drugs (ongoing clinical trials) or developing innovative antiviral drugs (preclinical and clinical studies) This review presents a thorough analysis of repurposed drug admitted for compassionate use from a chemical structure-biological activity perspective highlighting the ADME (absorption, distribution, metabolism, and excretion) properties and the toxicophore groups linked to potential adverse effects A detailed pharmacological description of the novel potential anti-COVID-19 therapeutics was also included In addition, a comprehensible overview of SARS-CoV-2 infection in terms of general description and structure, mechanism of viral infection, and clinical impact was portrayed

Title: Animal models for emerging coronavirus: progress and new insights Content: The emergences of coronaviruses have caused a serious global public health problem because their infection in humans caused the severe acute respiratory disease and deaths. The outbreaks of lethal coronaviruses have taken place for three times within recent two decades (SARS-CoV in 2002, MERS-CoV in 2012 and SARS-CoV-2 in 2019). Much more serious than SARS-CoV in 2002, the current SARS-CoV-2 infection has been spreading to more than 213 countries, areas or territories and causing more than two million cases up to date (17 April 2020). Unfortunately, no vaccine and specific anti-coronavirus drugs are available at present time. Current clinical treatment at hand is inadequate to suppress viral replication and inflammation, and reverse organ failure. Intensive research efforts have focused on increasing our understanding of viral biology of SARS-CoV-2, improving antiviral therapy and vaccination strategies. The animal models are important for both the fundamental research and drug discovery of coronavirus. This review aims to summarize the animal models currently available for SARS-CoV and MERS-CoV, and their potential use for the study of SARS-CoV-2. We will discuss the benefits and caveats of these animal models and present critical findings that might guide the fundamental studies and urgent treatment of SARS-CoV-2-caused diseases.

Title: Current global vaccine and drug efforts against COVID-19: Pros and cons of bypassing animal trials Content: COVID-19 has become one of the biggest health concern, along with huge economic burden. With no clear remedies to treat the disease, doctors are repurposing drugs like chloroquine and remdesivir to treat COVID-19 patients. In parallel, research institutes in collaboration with biotech companies have identified strategies to use viral proteins as vaccine candidates for COVID-19. Although this looks promising, they still need to pass the test of challenge studies in animal models. As various models for SARS-CoV-2 are under testing phase, biotech companies have bypassed animal studies and moved to Phase I clinical trials. In view of the present outbreak, this looks a justified approach, but the problem is that in the absence of animal studies, we can never predict the outcomes in humans. Since animal models are critical for vaccine development and SARS-CoV-2 has different transmission dynamics, in this review we compare different animal models of SARS-CoV-2 with humans for their pathogenic, immune response and transmission dynamics that make them ideal models for vaccine testing for COVID-19. Another issue of using animal model is the ethics of using animals for research; thus, we also discuss the pros and cons of using animals for vaccine development studies.

Title: Current global vaccine and drug efforts against COVID-19: Pros and cons of bypassing animal trials. Content: COVID-19 has become one of the biggest health concern, along with huge economic burden. With no clear remedies to treat the disease, doctors are repurposing drugs like chloroquine and remdesivir to treat COVID-19 patients. In parallel, research institutes in collaboration with biotech companies have identified strategies to use viral proteins as vaccine candidates for COVID-19. Although this looks promising, they still need to pass the test of challenge studies in animal models. As various models for SARS-CoV-2 are under testing phase, biotech companies have bypassed animal studies and moved to Phase I clinical trials. In view of the present outbreak, this looks a justified approach, but the problem is that in the absence of animal studies, we can never predict the outcomes in humans. Since animal models are critical for vaccine development and SARS-CoV-2 has different transmission dynamics, in this review we compare different animal models of SARS-CoV-2 with humans for their pathogenic, immune response and transmission dynamics that make them ideal models for vaccine testing for COVID-19. Another issue of using animal model is the ethics of using animals for research; thus, we also discuss the pros and cons of using animals for vaccine development studies.

Title: Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo Content: Background The outbreak of SARS CoV-2 has caused ever-increasing attention and public panic all over the world. Currently, there is no specific treatment against the SARS CoV-2. Therefore, identifying effective antiviral agents to combat the disease is urgently needed. Previous studies found that indomethacin has the ability to inhibit the replication of several unrelated DNA and RNA viruses, including SARS-CoV. Methods SARS CoV-2 pseudovirus-infected African green monkey kidney VERO E6 cells treated with different concentrations of indomethacin or aspirin at 48 hours post infection (p.i). The level of cell infection was determined by luciferase activity. Anti-coronavirus efficacy in vivo was confirmed by evaluating the time of recovery in canine coronavirus (CCV) infected dogs treated orally with 1mg/kg body weight indomethacin. Results We found that indomethacin has a directly and potently antiviral activity against the SARS CoV-2 pseudovirus (reduce relative light unit to zero). In CCV-infected dogs, recovery occurred significantly sooner with symptomatic treatment + oral indomethacin (1 mg/kg body weight) daily treatments than with symptomatic treatment + ribavirin (10-15 mg/kg body weight) daily treatments (P =0.0031), but was not significantly different from that with symptomatic treatment + anti-canine coronavirus serum + canine hemoglobin + canine blood immunoglobulin + interferon treatments (P =0.7784). Conclusion The results identify indomethacin as a potent inhibitor of SARS CoV-2.

Title: Feasibility of Known RNA Polymerase Inhibitors as Anti-SARS-CoV-2 Drugs Content: Coronaviruses (CoVs) are positive-stranded RNA viruses that infect humans and animals. Infection by CoVs such as HCoV-229E, -NL63, -OC43 and -HKU1 leads to the common cold, short lasting rhinitis, cough, sore throat and fever. However, CoVs such as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and the newest SARS-CoV-2 (the causative agent of COVID-19) lead to severe and deadly diseases with mortality rates ranging between ~1 to 35% depending on factors such as age and pre-existing conditions. Despite continuous global health threats to humans, there are no approved vaccines or drugs targeting human CoVs, and the recent outbreak of COVID-19 emphasizes an urgent need for therapeutic interventions. Using computational and bioinformatics tools, here we present the feasibility of reported broad-spectrum RNA polymerase inhibitors as anti- SARS-CoV-2 drugs targeting its main RNA polymerase, suggesting that investigational and approved nucleoside RNA polymerase inhibitors have potential as anti-SARS-CoV-2 drugs. However, we note that it is also possible for SARS-CoV-2 to evolve and acquire drug resistance mutations against these nucleoside inhibitors.

Title: Evaluation of 19 antiviral drugs against SARS-CoV-2 Infection Content: The global pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or 2019-nCoV) has prompted multiple clinical trials to jumpstart search for anti-SARS-CoV-2 therapies from existing drugs, including those with reported in vitro efficacies as well as those ones that are not known to inhibit SARS-CoV-2, such as ritonavir/lopinavir and favilavir. Here we report that after screening 19 antiviral drugs that are either in clinical trials or with proposed activity against SARS-CoV-2, remdesivir was the most effective. Chloroquine only effectively protected virus-induced cytopathic effect at around 30 µM with a therapeutic index of 1.5. Our findings also suggest that velpatasvir, ledipasvir, ritonavir, litonavir, lopinavir, favilavir, sofosbuvir, danoprevir, and pocapavir do not have direct antiviral effect.

Title: Candidate drugs against SARS-CoV-2 and COVID-19 Content: Abstract Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may prevent spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.

Title: Repurposing old drugs as antiviral agents for coronaviruses Content: BACKGROUND: New therapeutic options to address the ongoing COVID-19 pandemic are urgently needed. One possible strategy is the repurposing of existing drugs approved for other indications as antiviral agents for SARS-CoV-2. Due to the commercial unavailability of SARS-CoV-2 drugs for treating COVID-19, we screened approximately 250 existing drugs or pharmacologically active compounds for their inhibitory activities against feline infectious peritonitis coronavirus (FIPV) and human coronavirus OC43 (HCoV-OC43), a human coronavirus in the same genus (Betacoronavirus) as SARS-CoV-2. METHODS: FIPV was proliferated in feline Fcwf-4 cells and HCoV-OC43 in human HCT-8 cells. Viral proliferation was assayed by visualization of cytopathic effects on the infected Fcwf-4 cells and immunofluorescent assay for detection of the nucleocapsid proteins of HCoV-OC43 in the HCT-8 cells. The concentrations (EC(50)) of each drug necessary to diminish viral activity to 50% of that for the untreated controls were determined. The viabilities of Fcwf-4 and HCT-8 cells were measured by crystal violet staining and MTS/PMS assay, respectively. RESULTS: Fifteen out of the 252 drugs or pharmacologically active compounds screened were found to be active against both FIPV and HCoV-OC43, with EC(50) values ranging from 11 nM to 75 μM. They are all old drugs as follows, anisomycin, antimycin A, atovaquone, chloroquine, conivaptan, emetine, gemcitabine, homoharringtonine, niclosamide, nitazoxanide, oligomycin, salinomycin, tilorone, valinomycin, vismodegib. CONCLUSION: All of the old drugs identified as having activity against FIPV and HCoV-OC43 have seen clinical use in their respective indications and are associated with known dosing schedules and adverse effect or toxicity profiles in humans. Those, when later confirmed to have an anti-viral effect on SARS-CoV-2, should be considered for immediate uses in COVID-19 patients.

Title: Candidate drugs against SARS-CoV-2 and COVID-19 Content: Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may limit spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.

Title: Repurposing cefuroxime for treatment of COVID-19: a scoping review of in silico studies Content: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 19 (COVID-19), is a novel human Coronavirus that is responsible for about 300,000 deaths worldwide. To date, there is no confirmed treatment or vaccine prevention strategy against COVID-19. Due to the urgent need for effective treatment, drug repurposing is regarded as the immediate option. Potential drugs can often be identified via in silico drug screening experiments. Consequently, there has been an explosion of in silico experiments to find drug candidates or investigate anecdotal claims. One drug with several anecdotal accounts of benefit is Cefuroxime. The aim of this study was to identify and summarize in silico evidence for possible activity of Cefuroxime against SARS-CoV-2.To this end, we performed a scoping review of literature of in silico drug repurposing experiments for SARS-CoV-2 using PRISMA-ScR. We searched Medline, Embase, Scopus, Web of Knowledge, and Google Scholar for original studies published between 1st Feb, 2020 and 15th May, 2020 that screened drug libraries, and identified Cefuroxime as a top-ranked potential inhibitor drug against SARS-CoV-2 proteins. Six studies were identified. These studies reported Cefuroxime as a potential inhibitor of 3 key SARS-CoV-2 proteins; main protease, RNA dependent RNA polymerase, and ACE2-Spike complex. We provided a summary of the methodology and findings of the identified studies. Our scoping review identified significant in silico evidence that Cefuroxime may be a potential multi-target inhibitor of SARS-CoV-2. Further in vitro and in vivo studies are required to evaluate the potential of Cefuroxime for COVID-19. Communicated by Ramaswamy H. Sarma

Title: COVID‐19 drug repurposing: Summary statistics on current clinical trials and promising untested candidates Content: Repurposing of existing antiviral drugs, immunological modulators, and supportive therapies represents a promising path toward rapidly developing new control strategies to mitigate the devastating public health consequences of the COVID‐19 pandemic. A comprehensive text‐mining and manual curation approach was used to comb and summarize the most pertinent information from existing clinical trials and previous efforts to develop therapies against related betacoronaviruses, particularly SARS and MERS. In contrast to drugs in current trials, which have been derived overwhelmingly from studies on taxonomically unrelated RNA viruses, a number of untested small molecule antivirals had previously demonstrated remarkable in vitro specificity for SARS‐CoV or MERS‐CoV, with high selectivity indices, EC(50), and/or IC(50). Due to the rapid containment of the prior epidemics, however, these were generally not followed up with in vivo animal studies or clinical investigations, and thus largely overlooked as treatment prospects in the current COVID‐19 trials. This brief review summarizes and tabulates core information on recent or ongoing drug repurposing‐focused clinical trials, while detailing the most promising untested candidates with prior documented success against the etiologic agents of SARS and/or MERS.

Title: Repurposing cefuroxime for treatment of COVID-19: a scoping review of in silico studies Content: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 19 (COVID-19), is a novel human Coronavirus that is responsible for about 300,000 deaths worldwide. To date, there is no confirmed treatment or vaccine prevention strategy against COVID-19. Due to the urgent need for effective treatment, drug repurposing is regarded as the immediate option. Potential drugs can often be identified via in silico drug screening experiments. Consequently, there has been an explosion of in silico experiments to find drug candidates or investigate anecdotal claims. One drug with several anecdotal accounts of benefit is Cefuroxime. The aim of this study was to identify and summarize in silico evidence for possible activity of Cefuroxime against SARS-CoV-2.To this end, we performed a scoping review of literature of in silico drug repurposing experiments for SARS-CoV-2 using PRISMA-ScR. We searched Medline, Embase, Scopus, Web of Knowledge, and Google Scholar for original studies published between 1st Feb, 2020 and 15th May, 2020 that screened drug libraries, and identified Cefuroxime as a top-ranked potential inhibitor drug against SARS-CoV-2 proteins. Six studies were identified. These studies reported Cefuroxime as a potential inhibitor of 3 key SARS-CoV-2 proteins; main protease, RNA dependent RNA polymerase, and ACE2-Spike complex. We provided a summary of the methodology and findings of the identified studies. Our scoping review identified significant in silico evidence that Cefuroxime may be a potential multi-target inhibitor of SARS-CoV-2. Further in vitro and in vivo studies are required to evaluate the potential of Cefuroxime for COVID-19.Communicated by Ramaswamy H. Sarma.

Title: The potential of drug repositioning as a short-term strategy for the control and treatment of COVID-19 (SARS-CoV-2): a systematic review Content: The novel human coronavirus (SARS-CoV-2), the causative agent of COVID-19, has quickly become a threat to the public health and economy worldwide. Despite the severity of some cases, there are no current pathogen-specific antivirals available to treat the disease. Therefore, many studies have focused on the evaluation of the anti-SARS-CoV-2 activity of clinically available drugs. Here, we conducted a systematic review to describe the drug repositioning strategy against SARS-CoV-2 and to discuss the clinical impact of this approach in the current pandemic context. The systematic review was performed on March 23, 2020, using PubMed/MEDLINE, Scopus, Cochrane Library, and Biblioteca Virtual de Saúde (BVS). The data were summarized in tables and critically analyzed. After the database search, 12 relevant studies were identified as eligible for the review. Among the drugs reported in these studies, 57 showed some evidence of antiviral activity. Antivirals, especially antiretrovirals, are the main class of therapeutic agents evaluated against COVID-19. Moreover, studies have reported the anti-SARS-CoV-2 activity of antitumor (16%; 9/57), antimalarial (7%, 4/57), and antibacterial (5%; 3/57) agents. Additionally, seven pharmacological agents (chloroquine, tetrandrine, umifenovir (arbidol), carrimycin, damageprevir, lopinavir/ritonavir) are in phase IV of clinical trials. Due to the evidence of the anti-SARS-CoV-2 activity of various clinically available agents, drug repositioning stands out as a promising strategy for a short-term response in the fight against the novel coronavirus. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00705-020-04693-5) contains supplementary material, which is available to authorized users.

Title: Computational Models Identify Several FDA Approved or Experimental Drugs as Putative Agents Against SARS-CoV-2. Content: The outbreak of a novel human coronavirus (SARS-CoV-2) has evolved into global health emergency, infecting hundreds of thousands of people worldwide. We have identified experimental data on the inhibitory activity of compounds tested against closely related (96% sequence identity, 100% active site conservation) protease of SARS-CoV and employed this data to build QSAR models for this dataset. We employed these models for virtual screening of all drugs from DrugBank, including compounds in clinical trials. Molecular docking and similarity search approaches were explored in parallel with QSAR modeling, but molecular docking failed to correctly discriminate between experimentally active and inactive compounds. As a result of our studies, we recommended 41 approved, experimental, or investigational drugs as potential agents against SARS-CoV-2 acting as putative inhibitors of Mpro. Ten compounds with feasible prices were purchased and are awaiting the experimental validation..

Title: Repurposing old drugs as antiviral agents for coronaviruses Content: BACKGROUND: New therapeutic options to address the ongoing coronavirus disease 2019 (COVID-19) pandemic are urgently needed. One possible strategy is the repurposing of existing drugs approved for other indications as antiviral agents for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Due to the commercial unavailability of SARS-CoV-2 drugs for treating COVID-19, we screened approximately 250 existing drugs or pharmacologically active compounds for their inhibitory activities against feline infectious peritonitis coronavirus (FIPV) and human coronavirus OC43 (HCoV-OC43), a human coronavirus in the same genus (Betacoronavirus) as SARS-CoV-2. METHODS: FIPV was proliferated in feline Fcwf-4 cells and HCoV-OC43 in human HCT-8 cells. Viral proliferation was assayed by visualization of cytopathic effects on the infected Fcwf-4 cells and immunofluorescent assay for detection of the nucleocapsid proteins of HCoV-OC43 in the HCT-8 cells. The concentrations (EC50) of each drug necessary to diminish viral activity to 50% of that for the untreated controls were determined. The viabilities of Fcwf-4 and HCT-8 cells were measured by crystal violet staining and MTS/PMS assay, respectively. RESULTS: Fifteen out of the 252 drugs or pharmacologically active compounds screened were found to be active against both FIPV and HCoV-OC43, with EC50 values ranging from 11 nM to 75 µM. They are all old drugs as follows, anisomycin, antimycin A, atovaquone, chloroquine, conivaptan, emetine, gemcitabine, homoharringtonine, niclosamide, nitazoxanide, oligomycin, salinomycin, tilorone, valinomycin, and vismodegib. CONCLUSION: All of the old drugs identified as having activity against FIPV and HCoV-OC43 have seen clinical use in their respective indications and are associated with known dosing schedules and adverse effect or toxicity profiles in humans. Those, when later confirmed to have an anti-viral effect on SARS-CoV-2, should be considered for immediate uses in COVID-19 patients.

Title: COVID-19 drug repurposing: Summary statistics on current clinical trials and promising untested candidates Content: Repurposing of existing antiviral drugs, immunological modulators, and supportive therapies represents a promising path toward rapidly developing new control strategies to mitigate the devastating public health consequences of the COVID-19 pandemic. A comprehensive text-mining and manual curation approach was used to comb and summarize the most pertinent information from existing clinical trials and previous efforts to develop therapies against related betacoronaviruses, particularly SARS and MERS. In contrast to drugs in current trials, which have been derived overwhelmingly from studies on taxonomically unrelated RNA viruses, a number of untested small molecule antivirals had previously demonstrated remarkable in vitro specificity for SARS-CoV or MERS-CoV, with high selectivity indices, EC50 , and/or IC50 . Due to the rapid containment of the prior epidemics, however, these were generally not followed up with in vivo animal studies or clinical investigations, and thus largely overlooked as treatment prospects in the current COVID-19 trials. This brief review summarizes and tabulates core information on recent or ongoing drug repurposing-focused clinical trials, while detailing the most promising untested candidates with prior documented success against the etiologic agents of SARS and/or MERS.

Title: Machine Learning Models Identify Inhibitors of SARS-CoV-2 Content: With the ongoing SARS-CoV-2 pandemic there is an urgent need for the discovery of a treatment for the coronavirus disease (COVID-19). Drug repurposing is one of the most rapid strategies for addressing this need and numerous compounds have been selected for in vitro testing by several groups already. These have led to a growing database of molecules with in vitro activity against the virus. Machine learning models can assist drug discovery through prediction of the best compounds based on previously published data. Herein we have implemented several machine learning methods to develop predictive models from recent SARS-CoV-2 in vitro inhibition data and used them to prioritize additional FDA approved compounds for in vitro testing selected from our in-house compound library. From the compounds predicted with a Bayesian machine learning model, CPI1062 and CPI1155 showed antiviral activity in HeLa-ACE2 cell-based assays and represent potential repurposing opportunities for COVID-19. This approach can be greatly expanded to exhaustively virtually screen available molecules with predicted activity against this virus as well as a prioritization tool for SARS-CoV-2 antiviral drug discovery programs. The very latest model for SARS-CoV-2 is available at www.assaycentral.org.

Title: Discovery of clinically approved drugs capable of inhibiting SARS-CoV-2 in vitro infection using a phenotypic screening strategy and network-analysis to predict their potential to treat covid-19 Content: The disease caused by SARS-CoV2, covid-19, rapidly spreads worldwide, causing the greatest threat to global public health in the last 100 years. This scenario has become catastrophic as there are no approved vaccines to prevent the disease, and the main measures to contain the virus transmission are confinement and social distancing. One priority strategy is based on drug repurposing by pursuing antiviral chemotherapy that can control transmission and prevent complications associated with covid-19. With this aim, we performed a high content screening assay for the discovery of anti-SARS-CoV-2 compounds. From the 65 screened compounds, we have found four drugs capable to selectively inhibit SARS-CoV-2 in vitro infection: brequinar, abiraterone acetate, neomycin, and the extract of Hedera helix. Brequinar and abiraterone acetate had higher inhibition potency against SARS-CoV-2 than neomycin and Hedera helix extract, respectively. Drugs with reported antiviral activity and in clinical trials for covid-19, chloroquine, ivermectin, and nitazoxanide, were also included in the screening, and the last two were found to be non-selective. We used a data mining approach to build drug-host molecules-biological function-disease networks to show in a holistic way how each compound is interconnected with host node molecules and virus infection, replication, inflammatory response, and cell apoptosis. In summary, the present manuscript identified four drugs with active inhibition effect on SARS-CoV-2 in vitro infection, and by network analysis, we provided new insights and starting points for the clinical evaluation and repurposing process to treat SARS-CoV-2 infection. Summary sentence Discovery of drug repurposing candidates, inhibitors of SARS-CoV-2 infection in vitro, using a phenotypic screening strategy and network analysis.

Title: SARS-CoV-2: Recent Reports on Antiviral Therapies Based on Lopinavir/Ritonavir, Darunavir/Umifenovir, Hydroxychloroquine, Remdesivir, Favipiravir and Other Drugs for the Treatment of the New Coronavirus Content: Here we report on the most recent updates on experimental drugs successfully em- ployed in the treatment of the disease caused by SARS-CoV-2 coronavirus, also referred to as COVID-19 (COronaVIrus Disease 19). In particular, several cases of recovered patients have been reported after being treated with lopinavir/ritonavir (which is widely used to treat human immunodeficiency virus (HIV) infection) in combination with the anti-flu drug oseltamivir. In addition, remdesivir, which has been previously administered to Ebola virus patients, has also proven effective in the U.S. against coronavirus, while antimalarial chloroquine and hydroxy- chloroquine, favipiravir and co-administered darunavir and umifenovir (in patient therapies) were also recently recorded as having anti-SARS-CoV-2 effects. Since the recoveries/deaths ratio in the last weeks significantly increased, especially in China, it is clear that the experi- mental antiviral therapy, together with the availability of intensive care unit beds in hospitals and rigorous government control measures, all play an important role in dealing with this vi- rus. This also stresses the urgent need for the scientific community to devote its efforts to the development of other more specific antiviral strategies.

Title: Therapeutic Options for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Infection: How Close Are We? Content: Over 1100 cases of MERS-CoV have been reported since it was first identified in June 2012. Clinical presentation ranges from asymptomatic or mild illness to rapidly progressive disease with multi-organ failure and high mortality. Treatment has been largely supportive. A large number of compounds have been shown to have significant in vitro inhibitory activity against MERS-CoV. Until recently, macaques were the only suitable animal models for animal studies, hindering further clinical development of MERS-CoV therapy. However, the recent successful development of MERS-CoV infection model in transduced mice offers opportunities to accelerate clinical development of therapeutic agents for MERS-CoV infection. Currently available evidence supports further clinical investigation of interferon-based treatment regimens for patients with MERS-CoV. Combining interferon with mycophenolate and/or high-dose ribavirin appears especially promising. Monoclonal antibodies against various targets within MERS-CoV Spike protein have yielded encouraging in-vitro results. However, their safety and efficacy require confirmation in animal models and exploratory clinical trials.

Title: [Pharmacotherapy of severe acute respiratory syndrome (SARS)]. Content: Severe acute respiratory syndrome (SARS) constitutes the first new infectious disease of the current millennium. It is caused by the novel SARS-Coronavirus (SARS-CoV). SARS is related to a high morbidity and mortality and first appeared during an epidemic in 2002 - 2003. To date no specific therapy against the SARS-CoV is available. Due to the rapid spread of SARS during the epidemics in 2002 - 2003, randomised and controlled multicentre studies were not performed. Therefore, general guidelines have not been developed. Since the outbreak, scientists have been testing potential antiviral substances using in vitro and animal models. This study analyses the presently available in vitro and in vivo data on the pharmacotherapy of SARS.

Title: A Review on SARS-CoV-2 Virology, Pathophysiology, Animal Models, and Anti-Viral Interventions Content: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of CoV disease 2019 (COVID-19) is a highly pathogenic and transmissible CoV that is presently plaguing the global human population and economy. No proven effective antiviral therapy or vaccine currently exists, and supportive care remains to be the cornerstone treatment. Through previous lessons learned from SARS-CoV-1 and MERS-CoV studies, scientific groups worldwide have rapidly expanded the knowledge pertaining to SARS-CoV-2 virology that includes in vitro and in vivo models for testing of antiviral therapies and randomized clinical trials. In the present narrative, we review SARS-CoV-2 virology, clinical features, pathophysiology, and animal models with a specific focus on the antiviral and adjunctive therapies currently being tested or that require testing in animal models and randomized clinical trials.

Title: Dermatological therapies with relevance to COVID‐19 Content: SARS‐CoV‐2 is a novel single stranded RNA virus that has gripped humanity all over. It affects primarily the respiratory system, but is not limited to it, causing widespread involvement of many organ systems. The cases are still rising at an exponential rate and manifold trials are on to test different agents with the hope for potential limitation of spread and control of symptoms. Various classes of drugs have been tried; some with moderate success while many are yet to be proven to be of definite benefit. We have observed that the drugs used in dermatology practice are featured in more than a few of such studies. Here we wish to highlight the ones that we are familiar with, which has featured at some point, in the management of this very challenging pandemic. This article is protected by copyright. All rights reserved.

Title: Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19) Content: The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signals an urgent need for an expansion in treatment options. In this study, we investigated the anti-SARS-CoV-2 activities of 22 antiviral agents with known broad-spectrum antiviral activities against coronaviruses and/or other viruses. They were first evaluated in our primary screening in VeroE6 cells and then the most potent anti-SARS-CoV-2 antiviral agents were further evaluated using viral antigen expression, viral load reduction, and plaque reduction assays. In addition to remdesivir, lopinavir, and chloroquine, our primary screening additionally identified types I and II recombinant interferons, 25-hydroxycholesterol, and AM580 as the most potent anti-SARS-CoV-2 agents among the 22 antiviral agents. Betaferon (interferon-ß1b) exhibited the most potent anti-SARS-CoV-2 activity in viral antigen expression, viral load reduction, and plaque reduction assays among the recombinant interferons. The lipogenesis modulators 25-hydroxycholesterol and AM580 exhibited EC50 at low micromolar levels and selectivity indices of >10.0. Combinational use of these host-based antiviral agents with virus-based antivirals to target different processes of the SARS-CoV-2 replication cycle should be evaluated in animal models and/or clinical trials.

Title: Natural History of COVID-19 and Current Knowledge on Treatment Therapeutic Options Content: Despite intense research there is currently no effective vaccine available against the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in the later 2019 and responsible for the COVID-19 pandemic. This infectious and communicable disease has become one of the major public health challenges in the world. The clinical management of COVID-19 has been limited to infection prevention and control measures associated with supportive care such as supplemental oxygen and mechanical ventilation. Meanwhile efforts to find an effective treatment to inhibit virus replication, mitigate the symptoms, increase survival and decrease mortality rate are ongoing. Several classes of drugs, many of them already in use for other diseases, are being evaluated based on the body of clinical knowledge obtained from infected patients regarding to the natural history and evolution of the infection. Herein we will provide an updated overview of the natural history and current knowledge on drugs and therapeutic agents being tested for the prevention and treatment of COVID-19. These include different classes of drugs such as antiviral agents (chloroquine, ivermectin, nitazoxanide, hydroxychloroquine, lopinavir, remdesivir, tocilizumab), supporting agents (Vitamin C, Vitamin D, azithromycin, corticosteroids) and promising investigational vaccines. Considering the controversies and excessive number of compounds being tested and reported in the literature we hope that this review can provide useful and updated consolidated information on potential drugs used to prevent, control and treat COVID-19 patients worldwide.

Title: Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19). Content: The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signals an urgent need for an expansion in treatment options. In this study, we investigated the anti-SARS-CoV-2 activities of 22 antiviral agents with known broad-spectrum antiviral activities against coronaviruses and/or other viruses. They were first evaluated in our primary screening in VeroE6 cells and then the most potent anti-SARS-CoV-2 antiviral agents were further evaluated using viral antigen expression, viral load reduction, and plaque reduction assays. In addition to remdesivir, lopinavir, and chloroquine, our primary screening additionally identified types I and II recombinant interferons, 25-hydroxycholesterol, and AM580 as the most potent anti-SARS-CoV-2 agents among the 22 antiviral agents. Betaferon (interferon-β1b) exhibited the most potent anti-SARS-CoV-2 activity in viral antigen expression, viral load reduction, and plaque reduction assays among the recombinant interferons. The lipogenesis modulators 25-hydroxycholesterol and AM580 exhibited EC50 at low micromolar levels and selectivity indices of >10.0. Combinational use of these host-based antiviral agents with virus-based antivirals to target different processes of the SARS-CoV-2 replication cycle should be evaluated in animal models and/or clinical trials.

Title: A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals Content: The emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, more than 2.1 million confirmed cases and 139,500 deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. As the development of a vaccine could require at least 12-18 months, and the typical timeline from hit finding to drug registration of an antiviral is >10 years, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. Here, we report the identification of 30 known drugs that inhibit viral replication. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment.

Title: In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication Content: A novel coronavirus, named SARS-CoV-2, emerged in 2019 from Hubei region in China and rapidly spread worldwide. As no approved therapeutics exists to treat Covid-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time consuming stages of drug development. In this study, we screened the Prestwick Chemical Library® composed of 1,520 approved drugs in an infected cell-based assay. 90 compounds were identified. The robustness of the screen was assessed by the identification of drugs, such as Chloroquine derivatives and protease inhibitors, already in clinical trials. The hits were sorted according to their chemical composition and their known therapeutic effect, then EC50 and CC50 were determined for a subset of compounds. Several drugs, such as Azithromycine, Opipramol, Quinidine or Omeprazol present antiviral potency with 2<EC50<20µM. By providing new information on molecules inhibiting SARS-CoV-2 replication in vitro, this study could contribute to the short-term repurposing of drugs against Covid-19.

Title: Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets Content: Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect in vivo virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients.IMPORTANCE The SARS-CoV-2 pandemic continues to spread worldwide, with rapidly increasing numbers of mortalities, placing increasing strain on health care systems. Despite serious public health concerns, no effective vaccines or therapeutics have been approved by regulatory agencies. In this study, we tested the FDA-approved drugs lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir against SARS-CoV-2 infection in a highly susceptible ferret infection model. While most of the drug treatments marginally reduced clinical symptoms, they did not reduce virus titers, with the exception of emtricitabine-tenofovir treatment, which led to diminished virus titers in nasal washes at 8 dpi. Further, the azathioprine-treated immunosuppressed ferrets showed delayed virus clearance and low SN titers, resulting in a prolonged infection. As several FDA-approved or repurposed drugs are being tested as antiviral candidates at clinics without sufficient information, rapid preclinical animal studies should proceed to identify therapeutic drug candidates with strong antiviral potential and high safety prior to a human efficacy trial.

Title: Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19 Content: The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly translated to clinical care. Unfortunately, traditional drug discovery methods have a >90% failure rate and can take 10–15 years from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious single agents and combination therapies against SARS-CoV-2. Quantitative high-content morphological profiling was coupled with an AI-based machine learning strategy to classify features of cells for infection and stress. This assay detected multiple antiviral mechanisms of action (MOA), including inhibition of viral entry, propagation, and modulation of host cellular responses. From a library of 1,425 FDA-approved compounds and clinical candidates, we identified 16 dose-responsive compounds with antiviral effects. In particular, we discovered that lactoferrin is an effective inhibitor of SARS-CoV-2 infection with an IC(50) of 308 nM and that it potentiates the efficacy of both remdesivir and hydroxychloroquine. Lactoferrin also stimulates an antiviral host cell response and retains inhibitory activity in iPSC-derived alveolar epithelial cells, a model for the primary site of infection. Given its safety profile in humans, these data suggest that lactoferrin is a readily translatable therapeutic adjunct for COVID-19. Additionally, several commonly prescribed drugs were found to exacerbate viral infection and warrant clinical investigation. We conclude that morphological profiling for drug repurposing is an effective strategy for the selection and optimization of drugs and drug combinations as viable therapeutic options for COVID-19 pandemic and other emerging infectious diseases.

Title: Identification of five antiviral compounds from the Pandemic Response Box targeting SARS-CoV-2 Content: With currently over 4 million confirmed cases worldwide, including more than 300’000 deaths, the current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has a major impact on the economy and health care system. Currently, a limited amount of prophylactic or therapeutic intervention options are available against SARS-CoV-2. In this study, we screened 400 compounds from the antimicrobial ‘Pandemic Response Box’ library for inhibiting properties against SARS-CoV-2. We identified sixteen compounds that potently inhibited SARS-CoV-2 replication, of which five compounds displayed equal or even higher antiviral activity compared to Remdesivir. These results show that five compounds should be further investigated for their mode of action, safety and efficacy against SARS-CoV-2. Highlights 400 compounds from the pandemic response box were tested for antiviral activity against SARS-CoV-2. 5 compounds had an equal or higher antiviral efficacy towards SARS-CoV-2, compared to the nucleoside analogue Remdesivir.

Title: Drug repositioning is an alternative for the treatment of coronavirus COVID-19 Content: Given the extreme importance of the current pandemic caused by COVID-19, and as scientists agree there is no identified pharmacological treatment, where possible, therapeutic alternatives are raised through drug repositioning. This paper presents a selection of studies involving drugs from different pharmaceutical classes with activity against SARS-CoV-2 and SARS-CoV, with the potential for use in the treatment of COVID-19 disease.

Title: Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs Content: COVID-19 is an emerging infectious disease and was recently declared as a pandemic by WHO. Currently, there is no vaccine or therapeutic available for this disease. Drug repositioning represents the only feasible option to address this global challenge and a panel of 48 FDA-approved drugs that have been pre-selected by an assay of SARS-CoV was screened to identify potential antiviral drug candidates against SARS-CoV-2 infection. We found a total of 24 drugs which exhibited antiviral efficacy (0.1 μM < IC50 < 10 μM) against SARS-CoV-2. In particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects. These drugs will be tested in an appropriate animal model for their antiviral activities. In near future, these already FDA-approved drugs could be further developed following clinical trials in order to provide additional therapeutic options for patients with COVID-19.

Title: Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view Content: The broad-spectrum antiparasitic agent ivermectin has been very recently found to inhibit SARS-CoV-2 in vitro and proposed as a candidate for drug repurposing in COVID-19. In the present report the in vitro antiviral activity end-points are analyzed from the pharmacokinetic perspective. The available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations are not likely to be attainable in humans.

Title: Drug repositioning is an alternative for the treatment of coronavirus COVID-19 Content: Abstract Given the extreme importance of the current pandemic caused by COVID-19, and as scientists agree there is no identified pharmacological treatment, where possible, therapeutic alternatives are raised through drug repositioning. This paper presents a selection of studies involving drugs from different pharmaceutical classes with activity against SARS-CoV-2 and SARS-CoV, with the potential for use in the treatment of COVID-19 disease.

Title: SARS-CoV-2 RNA polymerase as target for antiviral therapy Content: A new human coronavirus named SARS-CoV-2 was identified in several cases of acute respiratory syndrome in Wuhan, China in December 2019. On March 11 2020, WHO declared the SARS-CoV-2 infection to be a pandemic, based on the involvement of 169 nations. Specific drugs for SARS-CoV-2 are obviously not available. Currently, drugs originally developed for other viruses or parasites are currently in clinical trials based on empiric data. In the quest of an effective antiviral drug, the most specific target for an RNA virus is the RNA-dependent RNA-polymerase (RdRp) which shows significant differences between positive-sense and negative-sense RNA viruses. An accurate evaluation of RdRps from different viruses may guide the development of new drugs or the repositioning of already approved antiviral drugs as treatment of SARS-CoV-2. This can accelerate the containment of the SARS-CoV-2 pandemic and, hopefully, of future pandemics due to other emerging zoonotic RNA viruses.

Title: Drug targets for COVID-19 therapeutics: Ongoing global efforts. Content: The current global pandemic COVID-19 caused by the SARS-CoV-2 virus has already inflicted insurmountable damage both to the human lives and global economy. There is an immediate need for identification of effective drugs to contain the disastrous virus outbreak. Global efforts are already underway at a war footing to identify the best drug combination to address the disease. In this review, an attempt has been made to understand the SARS-CoV-2 life cycle, and based on this information potential druggable targets against SARS-CoV-2 are summarized. Also, the strategies for ongoing and future drug discovery against the SARSCoV- 2 virus are outlined. Given the urgency to find a definitive cure, ongoing drug repurposing efforts being carried out by various organizations are also described. The unprecedented crisis requires extraordinary efforts from the scientific community to effectively address the issue and prevent further loss of human lives and health.

Title: Sensitivity of SARS/MERS CoV to interferons and other drugs based on achievable serum concentrations in humans. Content: A novel coronavirus (MERS-CoV) related to SARS-CoV recently emerged in the Middle East causing more than 400 deaths with a mortality rate of about 30%, much higher than SARS-CoV. Both viruses target epithelial cells in the respiratory tract, although utilizing different cellular receptors. Because of the sporadic nature of the MERS outbreak and difficulty in collecting randomized, controlled clinical data, the objective of this review was to focus on published in vitro and in vivo drug sensitivity data using both cell lines and available animal models of SARS/MERS CoV infection. Determination of drug activity was based on achievable serum levels in humans relative to in vitro IC50 (50% inhibitory concentration) or EC50 (50% effective concentration) drug concentrations. The most active drugs against SARS/MERS CoV at clinically achievable serum levels were type I interferons and a TLR3 agonist, interferon inducer/activator.

Title: Discovering drugs to treat coronavirus disease 2019 (COVID-19) Content: The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2.

Title: Discovering drugs to treat coronavirus disease 2019 (COVID-19). Content: The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2.

Title: In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2 Content: In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary. We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under evaluation in clinical trials for COVID-19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 μM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore further validation in more physiological models, yet they open up interesting avenues for the treatment of COVID-19.

Title: Current pharmacological modalities for management of novel coronavirus disease 2019 (COVID‐19) and the rationale for their utilization: A review Content: SARS‐CoV‐2 has caused a pandemic which is putting strain on the health‐care system and global economy. There is much pressure to develop both preventative and curative therapies for SARS‐CoV‐2 as there is no evidence to support therapies to improve outcomes in patients with SARS‐CoV‐2. Medications that inhibit certain steps of virus life cycle that are currently used to treat other illnesses such as Malaria, Ebola, HIV and Hepatitis C are being studied for use against SARS‐CoV‐2. To date, data is limited for medications that facilitate clinical improvement of COVID‐19 infections.

Title: Techniques used for the discovery of therapeutic compounds: The case of SARS Content: Severe acute respiratory syndrome coronavirus (SARS-CoV) is the etiological agent of SARS disease, which has ever severely menaced humans from the end of 2002 to June 2003. To date, great efforts have been made for the discovery of therapeutic compounds by using various technologies. In this report, we present a survey of these techniques and their applications in the development of promising anti-SARS agents. Section editors: Li-he Zhang – School of Pharmaceutical Science, Peking University, Beijing, China Kaixian Chen – Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

Title: An Update on Current Therapeutic Drugs Treating COVID-19 Content: The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presented unprecedented challenges to the healthcare systems in almost every country around the world. Currently, there are no proven effective vaccines or therapeutic agents against the virus. Current clinical management includes infection prevention and control measures and supportive care including supplemental oxygen and mechanical ventilatory support. Evolving research and clinical data regarding the virologic SARS-CoV-2 suggest a potential list of repurposed drugs with appropriate pharmacological effects and therapeutic efficacies in treating COVID-19 patients. In this review, we will update and summarize the most common and plausible drugs for the treatment of COVID-19 patients. These drugs and therapeutic agents include antiviral agents (remdesivir, hydroxychloroquine, chloroquine, lopinavir, umifenovir, favipiravir, and oseltamivir), and supporting agents (Ascorbic acid, Azithromycin, Corticosteroids, Nitric oxide, IL-6 antagonists), among others. We hope that this review will provide useful and most updated therapeutic drugs to prevent, control, and treat COVID-19 patients until the approval of vaccines and specific drugs targeting SARS-CoV-2.

Title: A pharmacological perspective of Chloroquine in SARS-CoV-2 infection Content: The pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is having serious consequences on health and the economy worldwide. All evidence-based treatment strategies need to be considered to combat this new virus. Drugs need to be considered on scientific grounds of efficacy, safety and cost. Chloroquine (CQ) and hydroxychloroquine (HCQ) are old drugs used in the treatment of malaria; in addition, their antiviral properties have been previously studied, including in coronaviruses, where evidence of efficacy has been found. The safety of CQ and HCQ has been studied for over 50 years. In the current race against time triggered by the SARS-CoV-2 pandemic, the search for new antivirals is very important. However, consideration should be given to old drugs with known anti-coronavirus activity, such as CQ and HCQ; these could be integrated into current treatment strategies while novel treatments are awaited, also in light of the fact that they display an anticoagulant effect that facilitates the activity of low MW heparin, aimed at preventing ARDS-associated thrombotic events. The safety of CQ and HCQ has been studied for over 50 years, however, recently published data raise concerns for cardiac toxicity of CQ/HCQ in patients with COVID-19. The review that we here provide also reexamines the real information provided by some of the published alarming reports although concluding that cardiac toxicity should in any case be stringently monitored with patients with CQ/HCQ.

Title: Elucidation on the Physicochemical Properties of Potential and Clinically Approved Antiviral Drugs: A Search for Effective Therapies against SARS-CoV-2 Infection Content: COVID-19 has been confirmed in millions of individuals worldwide, rendering it a global medical emergency In the absence of vaccines and the unavailability of effective drugs for the SARS-CoV-2 infection, vaccine development is being continuously explored and several antiviral compounds and immunotherapies are currently being investigated Given the high similarity in genetic identity between SARS-CoV and SARS-CoV-2, the present investigation identified the interaction between the physicochemical properties and the antiviral activity of different potential and clinically approved antiviral drugs against SARS-CoV using hierarchically weighted principal component analysis Representative drugs from the classes of neuraminidase inhibitors, reverse transcriptase inhibitors, protease inhibitors, nucleoside analogues, and other compounds with potential antiviral activity were examined The pharmacologic classification and the biological activity of the different antiviral drugs were described using indices, namely, rotatable bond count, molecular weight, heavy atom count, and molecular complexity (92 32% contribution rate) The physicochemical properties and inhibitory action against SARS-CoV-2 of lopinavir, chloroquine, ivermectin, and ciclesonide validated the adequacy of the current computational approach The findings of the present study provide additional information, although further investigation is warranted to identify potential targets and establish exact mechanisms, in the emergent search and design of antiviral drug candidates and their subsequent synthesis as effective therapies for COVID-19

Title: Indomethacin has a potent antiviral activity against SARS coronavirus. Content: UNLABELLED Severe acute respiratory syndrome (SARS) is a newly emerging, highly transmissible and fatal disease caused by a previously unknown coronavirus (SARS-CoV). Existing in non-identified animal reservoirs, SARS-CoV continues to represent a threat to humans because there is no effective specific antiviral therapy for coronavirus infections. OBJECTIVES Starting from the observation that cyclopentenone cyclooxygenase (COX) metabolites are active against several RNA viruses, we investigated the effect of the COX inhibitor indomethacin on coronavirus replication. METHODS Work involving infectious SARS-CoV was performed in biosafety level 3 facilities. SARS-CoV was grown in monkey VERO cells and human lung epithelial A549 cells, while canine coronavirus (CCoV) was grown in A72 canine cells. Antiviral activity was analysed by determining infective virus titres by TCID50, viral RNA synthesis by Northern blot analysis and real-time RT-PCR, and viral protein synthesis by SDS-PAGE analysis after 35S-methionine-labelling. Antiviral efficacy in vivo was determined by evaluating virus titres in CCoV-infected dogs treated orally with 1 mg/kg body weight indomethacin (INDO). RESULTS Unexpectedly, we found that INDO has a potent direct antiviral activity against the coronaviruses SARS-CoV and CCoV. INDO does not affect coronavirus binding or entry into host cells, but acts by blocking viral RNA synthesis at cytoprotective doses. This effect is independent of cyclooxygenase inhibition. INDO's potent antiviral activity (>1,000-fold reduction in virus yield) was confirmed in vivo in CCoV-infected dogs. CONCLUSIONS The results identify INDO as a potent inhibitor of coronavirus replication and suggest that, having both anti-inflammatory and antiviral activity, INDO could be beneficial in SARS therapy.

Title: In silico identification of clinically approved medicines against the main protease of SARS-CoV-2, causative agent of covid-19 Content: The COVID-19 pandemic triggered by SARS-CoV-2 is a worldwide health disaster. Main protease is an attractive drug target among coronaviruses, due to its vital role in processing the polyproteins that are translated from the viral RNA. There is presently no exact drug or treatment for this diseases caused by SARS-CoV-2. In the present study, we report the potential inhibitory activity of some FDA approved drugs against SARS-CoV-2 main protease by molecular docking study to investigate their binding affinity in protease active site. Docking studies revealed that drug Oseltamivir (anti-H1N1 drug), Rifampin (anti-TB drug), Maraviroc, Etravirine, Indinavir, Rilpivirine (anti-HIV drugs) and Atovaquone, Quinidine, Halofantrine, Amodiaquine, Tetracylcine, Azithromycin, hydroxycholoroquine (anti-malarial drugs) among others binds in the active site of the protease with similar or higher affinity. However, the in-silico abilities of the drug molecules tested in this study, further needs to be validated by carrying out in vitro and in vivo studies. Moreover, this study spreads the potential use of current drugs to be considered and used to comprise the fast expanding SARS-CoV-2 infection.

Title: Drug Repurposing to find Inhibitors of SARS-CoV-2 Main Protease Content: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the strain of coronavirus that causes coronavirus disease 2019 (COVID-19), the respiratory illness responsible for the COVID-19 pandemic. Currently there is no known vaccine or specific antiviral treatment for COVID-19 and so, there is an urgent need for expedite discovery of new therapeutics to combat the disease until a vaccine will be available worldwide. Drug repurposing is a strategy for identifying new uses for approved drugs that has the advantage (over conventional approaches that attempt to develop a drug from scratch) that time frame of the overall process can be significantly reduced because of the few number of clinical trial required. In this work, a virtual screening of FDA-approved drugs was performed for repositioning as potential inhibitors of the main protease Mpro of SARS-CoV-2. As a result of this study, 12 drugs are proposed as candidates for inhibitors of the Mpro enzyme. Some of the selected compounds are antiviral drugs that are already being tested in COVID-19 clinical trials (i.e. ribavirin) or are used to alleviate symptoms of the disease (i.e. codeine). Surprisingly, the most promising candidate is the naturally occurring broad spectrum antibiotic oxytetracycline. This compound has largely outperformed the remaining selected candidates along all filtering steps of our virtual screening protocol. If the activity of any of these drugs is experimentally corroborated, they could be used directly in clinical trials without the need for pre-clinical testing or safety evaluation since they are already used as drugs for other diseases.

Title: Inhibition of SARS Coronavirus Infection In Vitro with Clinically Approved Antiviral Drugs Content: Severe acute respiratory syndrome (SARS) is an infectious disease caused by a newly identified human coronavirus (SARS-CoV). Currently, no effective drug exists to treat SARS-CoV infection. In this study, we investigated whether a panel of commercially available antiviral drugs exhibit in vitro anti–SARS-CoV activity. A drug-screening assay that scores for virus-induced cytopathic effects on cultured cells was used. Tested were 19 clinically approved compounds from several major antiviral pharmacologic classes: nucleoside analogs, interferons, protease inhibitors, reverse transcriptase inhibitors, and neuraminidase inhibitors. Complete inhibition of cytopathic effects of SARS-CoV in culture was observed for interferon subtypes, β-1b, α-n1, α-n3, and human leukocyte interferon α. These findings support clinical testing of approved interferons for the treatment of SARS.

Title: Remdesivir, the antiviral hope against SARS-CoV-2/ Remdesivir, la esperanza antiviral frente al SARS-CoV-2 Content: On December 31, 2019 a pneumonia outbreak caused by a new coronavirus (SARS-CoV-2) was detected in the city of Wuhan (China) Due to the high capacity of diffusion and human infection it has become a new zoonotic pandemic The absence of a vaccine has determined the search for antiviral drugs with the capacity to inhibit the replication of the new virus Among them, remdesivir, an analogue of adenosine, is what seems to have a more promising future This drug has shown in vitro and in animals a high capacity to block infection and viral replication with attainable concentrations in human plasma Although all studies have been carried out with SARS-CoV and MERS-CoV, it seems that by virological and functional analogy, remdesivir is one of the few antiviral drugs with proven efficacy However, studies and clinical trials in humans are required to know the result of their application in them

Title: What do we know about remdesivir drug interactions? Content: The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS‐Co‐V‐2) has resulted in a critical need to rapidly develop new pharmacologic interventions and disseminate information. This has led to confusing and conflicting information on drug efficacy. Remdesivir has emerged as a promising treatment for SARS‐Co‐V‐2 infection yet published clinical pharmacology and drug interaction studies are limited. Additional studies of the disposition of remdesivir, its active metabolite (GS‐441524), and its triphosphate metabolite (GS‐443902) are needed.

Title: Available Evidence and Ongoing Clinical Trials of Remdesivir: Could It Be a Promising Therapeutic Option for COVID-19? Content: The novel coronavirus strain, severe acute respiratory syndrome coronavirus-2, the causative agent of COVID-19 emerged in Wuhan, China, in December 2019 and is skyrocketing throughout the globe and become a global public health emergency. Despite promising preventive measures being taken, there is no vaccine or drug therapy officially approved to prevent or treat the infection. Everybody is waiting the findings of ongoing clinical trials in various chemical and biological products. This review is specifically aimed to summarize the available evidence and ongoing clinical trials of remdesivir as a potential therapeutic option for COVID-19. Remdesivir is an investigational drug having broad spectrum antiviral activity with its target RNA dependent RNA polymerase. It has not yet been officially approved for Ebola and Coronaviruses. Several studies showed that remdesivir had promising in vitro and in vivo antiviral activities against SARS-CoV-1 and MERS-CoV strains. On the top of this, it exhibited a promising in vitro activity against SARS-CoV-2 strains though there are no published studies that substantiate its activity in vivo until the time of this review. There are few phase 3 randomized double-blind placebo controlled trials on the way to investigate the safety and efficacy of remdesivir. Of which, one completed double blind, placebo controlled trial showed that remdesivir showed faster time to clinical improvement in severe COVID-19 patients compared to placebo though not found statistically significant. In addition, two phase 3 randomized open label clinical trials coordinated by Gilead Sciences are being conducted. In addition, WHO Solidarity trial and INSERM DisCoVeRy trials (randomized open labels) were launched recently.

Title: Drug targets for COVID-19 therapeutics: Ongoing global efforts Content: The current global pandemic COVID-19 caused by the SARS-CoV-2 virus has already inflicted insurmountable damage both to the human lives and global economy. There is an immediate need for identification of effective drugs to contain the disastrous virus outbreak. Global efforts are already underway at a war footing to identify the best drug combination to address the disease. In this review, an attempt has been made to understand the SARS-CoV-2 life cycle, and based on this information potential druggable targets against SARS-CoV-2 are summarized. Also, the strategies for ongoing and future drug discovery against the SARS-CoV-2 virus are outlined. Given the urgency to find a definitive cure, ongoing drug repurposing efforts being carried out by various organizations are also described. The unprecedented crisis requires extraordinary efforts from the scientific community to effectively address the issue and prevent further loss of human lives and health.

Title: The Rationale for Potential Pharmacotherapy of COVID-19 Content: On 11 March 2020, the coronavirus disease (COVID-19) was defined by the World Health Organization as a pandemic. Severe acute respiratory syndrome-2 (SARS-CoV-2) is the newly evolving human coronavirus infection that causes COVID-19, and it first appeared in Wuhan, China in December 2019 and spread rapidly all over the world. COVID-19 is being increasingly investigated through virology, epidemiology, and clinical management strategies. There is currently no established consensus on the standard of care in the pharmacological treatment of COVID-19 patients. However, certain medications suggested for other diseases have been shown to be potentially effective for treating this infection, though there has yet to be clear evidence. Therapies include new agents that are currently tested in several clinical trials, in addition to other medications that have been repurposed as antiviral and immune-modulating therapies. Previous high-morbidity human coronavirus epidemics such as the 2003 SARS-CoV and the 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) prompted the identification of compounds that could theoretically be active against the emerging coronavirus SARS-CoV-2. Moreover, advances in molecular biology techniques and computational analysis have allowed for the better recognition of the virus structure and the quicker screening of chemical libraries to suggest potential therapies. This review aims to summarize rationalized pharmacotherapy considerations in COVID-19 patients in order to serve as a tool for health care professionals at the forefront of clinical care during this pandemic. All the reviewed therapies require either additional drug development or randomized large-scale clinical trials to be justified for clinical use.

Title: Protease Inhibitors: Candidate Drugs to Inhibit Severe Acute Respiratory Syndrome Coronavirus 2 Replication. Content: The number of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly increased, although the WHO declared a pandemic. However, drugs that function against SARS-CoV-2 have not been established. SARS-CoV-2 has been suggested to bind angiotensin-converting enzyme 2, the receptor of the SARS coronavirus. SARS coronavirus and coronavirus 229E, the cause of the common cold, replicate through cell-surface and endosomal pathways using a protease, the type II transmembrane protease. To examine the effects of protease inhibitors on the replication of coronavirus 229E, we pretreated primary cultures of human nasal epithelial (HNE) cells with camostat or nafamostat, each of which has been used for the treatment of pancreatitis and/or disseminated intravascular coagulation. HNE cells were then infected with coronavirus 229E, and viral titers in the airway surface liquid of the cells were examined. Pretreatment with camostat (0.1-10 μg/mL) or nafamostat (0.01-1 μg/mL) reduced the titers of coronavirus 229E. Furthermore, a significant amount of type II transmembrane protease protein was detected in the airway surface liquid of HNE cells. Additionally, interferons have been reported to have antiviral effects against SARS coronavirus. The additive effects of interferons on the inhibitory effects of other candidate drugs to treat SARS-CoV-2 infection, such as lopinavir, ritonavir and favipiravir, have also been studied. These findings suggest that protease inhibitors of this type may inhibit coronavirus 229E replication in human airway epithelial cells at clinical concentrations. Protease inhibitors, interferons or the combination of these drugs may become candidate drugs to inhibit the replication of SARS-CoV-2.

Title: Fight against novel coronavirus: A perspective of medicinal chemists Content: The ongoing novel coronavirus disease (COVID-19) pandemic makes us painfully perceive that our bullet shells are blank so far for fighting against severe human coronavirus (HCoV). In spite of vast research work, it is crystal clear that the evident does not warrant the commercial blossoming of anti-HCoV drugs. In this circumstance, drug repurposing and/or screening of databases are the only fastest option. This study is an initiative to recapitulate the medicinal chemistry of severe acute respiratory syndrome (SARS)-CoV-2 (SARS-CoV-2). The aim is to present an exquisite delineation of the current research from the perspective of a medicinal chemist to allow the rapid development of anti-SARS-CoV-2 agents.

Title: Potential therapeutic targets for combating SARS-CoV-2: Drug repurposing, clinical trials and recent advancements Content: The present pandemic of SARS-CoV-2 has been a tough task for the whole world to deal with. With the absence of specific drugs or vaccines against SARS-CoV-2, the situation is very difficult to control. Apart from the absence of specific therapies, the lack of knowledge about potential therapeutic targets and individual perception is adding to the complications. The present review describes the novel SARS-CoV-2 structure, surface proteins, asymptomatic and symptomatic transmission in addition to the genotype and phenotype of SARS-CoV-2 along with genetic strains and similarity between SARS, MERS and SARS-CoV-2. Therapeutic strategies such as inhibition of the endocytic pathway and suppressing RNA polymerase activity by metal ions, which could be quite beneficial for controlling COVID-19, are outlined. The drug repurposing for SARS-CoV-2 is discussed in detail along with therapeutic classes such as antivirals, antibiotics, and amino quinolones and their probable role in suppressing SARS-CoV-2 with reference to case studies. The ongoing clinical trials both with respect to drug repurposing and vaccines are summarized along with a brief description. The recent advancements and future perspective of ongoing research for therapy and detection of SARS-CoV-2 are provided. The review, in brief, summarizes epidemiology, therapy and the current scenario for combating SARS-CoV-2.

Title: Putative Inhibitors of SARS-CoV-2 Main Protease from A Library of Marine Natural Products: A Virtual Screening and Molecular Modeling Study Content: The current emergency due to the worldwide spread of the COVID-19 caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a great concern for global public health. Already in the past, the outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle Eastern respiratory syndrome (MERS) in 2012 demonstrates the potential of coronaviruses to cross-species borders and further underlines the importance of identifying new-targeted drugs. An ideal antiviral agent should target essential proteins involved in the lifecycle of SARS-CoV. Currently, some HIV protease inhibitors (i.e., Lopinavir) are proposed for the treatment of COVID-19, although their effectiveness has not yet been assessed. The main protease (M(pro)) provides a highly validated pharmacological target for the discovery and design of inhibitors. We identified potent M(pro) inhibitors employing computational techniques that entail the screening of a Marine Natural Product (MNP) library. MNP library was screened by a hyphenated pharmacophore model, and molecular docking approaches. Molecular dynamics and re-docking further confirmed the results obtained by structure-based techniques and allowed this study to highlight some crucial aspects. Seventeen potential SARS-CoV-2 M(pro) inhibitors have been identified among the natural substances of marine origin. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds could be bioactive is excellent.

Title: Potent antiviral effect of protoporphyrin IX and verteporfin on SARS-CoV-2 infection Content: The infection of SARS-CoV-2 has spread to more than 200 countries and regions and the numbers of infected people and deaths worldwide are expected to continue to rise. Current treatment of COVID-19 is limited and mostly supportive. At present, there is no specific therapeutics against SARS-CoV-2. In this study, we discovered that protoporphyrin IX and verteporfin, two FDA-approved drugs for treatment of human diseases, had significant antiviral effect against SARS-CoV-2, with EC50 values for the reduction of viral RNA at nanomolar concentrations. Both drugs completely inhibited the cytopathic effect (CPE) produced by SARS-CoV-2 infection at lower drug concentrations than that of remdesivir. The selection indices of protoporphyrin IX and verteporfin are 952.74 and 368.93, respectively, suggesting wide safety margins. Both drugs were able to prevent SARS-CoV-2 infection as well as suppress established SARS-CoV-2 infection. The compounds share a porphyrin ring structure. Molecular docking indicates that the compounds may interact with viral receptor ACE2 and could block the cell-cell fusion mediated by ACE2 and viral S protein. Our finding suggests that protoporphyrin IX and verteporfin might be potential antivirals against SARS-CoV-2 infection and also sheds new light on the development of a novel class of small compounds against SARS-CoV-2.

Title: A small molecule drug candidate targeting SARS-CoV-2 main protease Content: A new coronavirus identified as SARS-CoV-2 virus has brought the world to a state of crisis, causing a major pandemic, claiming more than 433,000 lives and instigating major financial damage to the global economy. Despite current efforts, developing safe and effective treatments remains a major challenge. Moreover, new strains of the virus are likely to emerge in the future. To prevent future pandemics, several drugs with various mechanisms of action are required. Drug discovery efforts against the virus fall into two main categories: (a) monoclonal antibodies targeting the spike protein of the virus and blocking it from entry; (b) small molecule inhibitors targeting key proteins of the virus, interfering with replication and translation of the virus. In this study, we are presenting a computational investigation of a potential drug candidate that targets SARS-CoV-2 protease, a viral protein critical for replication and translation of the virus.

Title: Repositioning of 8565 existing drugs for COVID-19 Content: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected near 5 million people and led to over 0.3 million deaths. Currently, there is no specific anti-SARS-CoV-2 medication. New drug discovery typically takes more than ten years. Drug repositioning becomes one of the most feasible approaches for combating COVID-19. This work curates the largest available experimental dataset for SARS-CoV-2 or SARS-CoV main protease inhibitors. Based on this dataset, we develop validated machine learning models with relatively low root mean square error to screen 1553 FDA-approved drugs as well as other 7012 investigational or off-market drugs in DrugBank. We found that many existing drugs might be potentially potent to SARS-CoV-2. The druggability of many potent SARS-CoV-2 main protease inhibitors is analyzed. This work offers a foundation for further experimental studies of COVID-19 drug repositioning.

Title: The journey of remdesivir: from Ebola to COVID-19 Content: Countries around the world are currently fighting the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a betacoronavirus, belonging to the same genus as severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV. Currently, there are no proven antiviral therapies for COVID-19. Numerous clinical trials have been initiated to identify an effective treatment. One leading candidate is remdesivir (GS-5734), a broad-spectrum antiviral that was initially developed for the treatment of Ebola virus (EBOV). Although remdesivir performed well in preclinical studies, it did not meet efficacy endpoints in a randomized trial conducted during an Ebola outbreak. Remdesivir holds promise for treating COVID-19 based on in vitro activity against SARS-CoV-2, uncontrolled clinical reports, and limited data from randomized trials. Overall, current data are insufficient to judge the efficacy of remdesivir for COVID-19, and the results of additional randomized studies are eagerly anticipated. In this narrative review, we provide an overview of Ebola and coronavirus outbreaks. We then summarize preclinical and clinical studies of remdesivir for Ebola and COVID-19.

Title: The pharmacological development of direct acting agents for emerging needed therapy against SARS-CoV-2 Content: Recently, the SARS-CoV-2 was quickly identified as the causal pathogen leading to the outbreak of severe acute respiratory syndrome-like illness all over the world. As the SARS-CoV-2 infection pandemic proceeds, many efforts are being dedicated to the development of diverse treatment strategies. Increasing evidence showed potential therapeutic agents directly acting against SARS-CoV-2 virus, such as interferon, RNA-dependent RNA polymerase inhibitors, protease inhibitors, viral entry blockers, neuraminidase inhibitor, vaccine, antibody agent targeting the SARS-CoV-2 RNA genome, natural killer cells and nucleocytoplasmic trafficking inhibitor. To date, several direct anti-SARS-CoV-2 agents have demonstrated promising in vitro and clinical efficacy. This article reviews the current and future development of direct acting agents against SARS-CoV-2.

Title: The pharmacological development of direct acting agents for emerging needed therapy against SARS-CoV-2. Content: Recently, the SARS-CoV-2 was quickly identified as the causal pathogen leading to the outbreak of severe acute respiratory syndrome-like illness all over the world. As the SARS-CoV-2 infection pandemic proceeds, many efforts are being dedicated to the development of diverse treatment strategies. Increasing evidence showed potential therapeutic agents directly acting against SARS-CoV-2 virus, such as interferon, RNA-dependent RNA polymerase inhibitors, protease inhibitors, viral entry blockers, neuraminidase inhibitor, vaccine, antibody agent targeting the SARS-CoV-2 RNA genome, natural killer cells and nucleocytoplasmic trafficking inhibitor. To date, several direct anti-SARS-CoV-2 agents have demonstrated promising in vitro and clinical efficacy. This article reviews the current and future development of direct acting agents against SARS-CoV-2.

Title: Protease Inhibitors: Candidate Drugs to Inhibit Severe Acute Respiratory Syndrome Coronavirus 2 Replication Content: The number of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly increased, although the WHO declared a pandemic. However, drugs that function against SARS-CoV-2 have not been established. SARS-CoV-2 has been suggested to bind angiotensin-converting enzyme 2, the receptor of the SARS coronavirus. SARS coronavirus and coronavirus 229E, the cause of the common cold, replicate through cell-surface and endosomal pathways using a protease, the type II transmembrane protease. To examine the effects of protease inhibitors on the replication of coronavirus 229E, we pretreated primary cultures of human nasal epithelial (HNE) cells with camostat or nafamostat, each of which has been used for the treatment of pancreatitis and/or disseminated intravascular coagulation. HNE cells were then infected with coronavirus 229E, and viral titers in the airway surface liquid of the cells were examined. Pretreatment with camostat (0.1-10 µg/mL) or nafamostat (0.01-1 µg/mL) reduced the titers of coronavirus 229E. Furthermore, a significant amount of type II transmembrane protease protein was detected in the airway surface liquid of HNE cells. Additionally, interferons have been reported to have antiviral effects against SARS coronavirus. The additive effects of interferons on the inhibitory effects of other candidate drugs to treat SARS-CoV-2 infection, such as lopinavir, ritonavir and favipiravir, have also been studied. These findings suggest that protease inhibitors of this type may inhibit coronavirus 229E replication in human airway epithelial cells at clinical concentrations. Protease inhibitors, interferons or the combination of these drugs may become candidate drugs to inhibit the replication of SARS-CoV-2.

Title: Hydroxychloroquine Proves Ineffective in Hamsters and Macaques Infected with SARS-CoV-2 Content: We remain largely without effective prophylactic/therapeutic interventions for COVID-19. Although many human clinical trials are ongoing, there remains a deficiency of supportive preclinical drug efficacy studies. Here we assessed the prophylactic/therapeutic efficacy of hydroxychloroquine (HCQ), a drug of interest for COVID-19 management, in two animal models. When used for prophylaxis or treatment neither the standard human malaria dose (6.5 mg/kg) nor a high dose (50 mg/kg) of HCQ had any beneficial effect on clinical disease or SARS-CoV-2 kinetics (replication/shedding) in the Syrian hamster disease model. Similarly, HCQ prophylaxis/treatment (6.5 mg/kg) did not significantly benefit clinical outcome nor reduce SARS-CoV-2 replication/shedding in the upper and lower respiratory tract in the rhesus macaque disease model. In conclusion, our preclinical animal studies do not support the use of HCQ in prophylaxis/treatment of COVID-19.

Title: A systematic review protocol of the antiviral activity of chloroquine and hydroxychloroquine against COVID-19. Content: Introduction: The recent outbreak of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), or COVID-19 with no approved medicines has led to global health threat. Currently, repositioning of old medicines seems the most responsible strategy for potential cure and prevention COVID-19. Hydroxychloroquine and chloroquine have shown promising efficacy against COVID-19 related pneumonia in clinical studies. However, the mode of drug action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection is not clear. This review aims to gather evidence on antiviral activity and possible mechanism of drug action of chloroquine and hydroxychloroquine on SARS-CoV-2, including in-vitro, animal studies, and studies in humans. Method: A structured search of five bibliographic databases namely; Medline, Web of Science, PubMed, Cochrane CENTRAL, and Google Scholar will be undertaken to retrieve studies that describe the antiviral activity and possible mechanism of drug action of chloroquine and hydroxychloroquine on SARS-CoV-2. No restrictions will be placed on publication date, but studies will be limited to only publications in English. Duplication of studies will be removed using EndNote reference manager. Three authors will screen the citations independently based on inclusion criteria. Data extraction and assessment of risk of bias will be done independently. Meta-analysis of selected studies will be done wherever suitable. Ethics and dissemination: Primary data collection will not be involved in this study, hence no need for formal ethical clearance. Findings from the study will be disseminated through a peer-reviewed publication and conference meeting. Trial registration number: https://doi.org/10.17605/OSF.IO/7DJMU

Title: A SARS-CoV-2 protein interaction map reveals targets for drug repurposing Content: A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

Title: Treatments for COVID-19: emerging drugs against the coronavirus Content: The Coronavirus disease 19 (COVID-19) outbreak has been recognized as a global threat to public health. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and no effective therapies currently exist against this novel viral agent. Along with extensive public health measures, an unprecedented global effort in identifying effective drugs for the treatment is being implemented. Potential drug targets are emerging as the result of a fast-evolving understanding of SARS-CoV-2 virology, host response to the infection, and clinical course of the disease. This brief review focuses on the latest and most promising pharmacological treatments against COVID-19 currently under investigation and discuss their potential use based on either documented efficacy in similar viral infections, or their activity against inflammatory syndromes. Ongoing clinical trials are also emphasized.

Title: Treatments for COVID-19: emerging drugs against the coronavirus. Content: The Coronavirus disease 19 (COVID-19) outbreak has been recognized as a global threat to public health. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and no effective therapies currently exist against this novel viral agent. Along with extensive public health measures, an unprecedented global effort in identifying effective drugs for the treatment is being implemented. Potential drug targets are emerging as the result of a fast-evolving understanding of SARS-CoV-2 virology, host response to the infection, and clinical course of the disease. This brief review focuses on the latest and most promising pharmacological treatments against COVID-19 currently under investigation and discuss their potential use based on either documented efficacy in similar viral infections, or their activity against inflammatory syndromes. Ongoing clinical trials are also emphasized.

Title: Harnessing the power of novel animal-free test methods for the development of COVID-19 drugs and vaccines Content: The COVID-19-inducing virus, SARS-CoV2, is likely to remain a threat to human health unless efficient drugs or vaccines become available. Given the extent of the current pandemic (people in over one hundred countries infected) and its disastrous effect on world economy (associated with limitations of human rights), speedy drug discovery is critical. In this situation, past investments into the development of new (animal-free) approach methods (NAM) for drug safety, efficacy, and quality evaluation can be leveraged. For this, we provide an overview of repurposing ideas to shortcut drug development times. Animal-based testing would be too lengthy, and it largely fails, when a pathogen is species-specific or if the desired drug is based on specific features of human biology. Fortunately, industry has already largely shifted to NAM, and some public funding programs have advanced the development of animal-free technologies. For instance, NAM can predict genotoxicity (a major aspect of carcinogenicity) within days, human antibodies targeting virus epitopes can be generated in molecular biology laboratories within weeks, and various human cell-based organoids are available to test virus infectivity and the biological processes controlling them. The European Medicines Agency (EMA) has formed an expert group to pave the way for the use of such approaches for accelerated drug development. This situation illustrates the importance of diversification in drug discovery strategies and clearly shows the shortcomings of an approach that invests 95% of resources into a single technology (animal experimentation) in the face of challenges that require alternative approaches. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00204-020-02787-2) contains supplementary material, which is available to authorized users.

Title: Animal Model Prescreening: Pre-exposure to SARS-CoV-2 impacts responses in the NHP model Content: COVID-19 presents herculean challenges to research and scientific communities for producing diagnostic and treatment solutions. Any return to normalcy requires rapid development of countermeasures, with animal models serving as a critical tool in testing vaccines and therapeutics. Animal disease status and potential COVID-19 exposure prior to study execution may severely bias efficacy testing. We developed a toolbox of immunological and molecular tests to monitor countermeasure impact on disease outcome and evaluate pre-challenge COVID-19 status. Assay application showed critical necessity for animal pre-screening. Specifically, real-time PCR results documented pre-exposure of an African Green Monkey prior to SARS-CoV-2 challenge with sequence confirmation as a community-acquired exposure. Longitudinal monitoring of nasopharyngeal swabs and serum showed pre-exposure impacted both viral disease course and resulting immunological response. This study demonstrates utility in a comprehensive pre-screening strategy for animal models, which captured the first documented case of community-acquired, non-human primate infection. One Sentence Summary Pre-exposure to SARS-CoV-2 affects biomarker responses in animal models, highlighting a need for robust pre-screening protocols prior to medical countermeasure studies.