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Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-Cov-2

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Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-Cov-2 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.06.188953; this version posted July 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Identification of potent and safe antiviral therapeutic candidates against 2 SARS-CoV-2 3 Xia Xiao1,2,3*, Conghui Wang1,2,3*, De Chang4*, Ying Wang1,2,3, Xiaojing Dong1,2,3, Tao Jiao1,2,3, 4 Zhendong Zhao1,2,3, Lili Ren1,2,3, Charles S Dela Cruz5, Lokesh Sharma5†, Xiaobo Lei1,2,3†, 5 Jianwei Wang1,2,3† 6 7 1NHC Key Laboratory of System Biology of Pathogens, Institute of Pathogen Biology, Chinese 8 Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P.R. China; 9 2Key Laboratory of Respiratory Pathogenomics, Chinese Academy of Medical Sciences, Beijing 10 100730, P.R. China; 11 3Christophe Merieux Laboratory, Institute of Pathogen Biology, C Chinese Academy of Medical 12 Sciences & Peking Union Medical College, Beijing 100730, P.R. China; 13 4 Third Medical Center of Chinese PLA General Hospital, Beijing, 100039, P. R. China 14 5 Section of Pulmonary and Critical Care and Sleep Medicine, Department of Medicine, Yale 15 University School of Medicine, New Haven, CT 06520, USA 16 * These authors contributed equally to this work. 17 † These authors also contributed equally to this work. 18 Corresponding to: 19 Dr. Jianwei Wang 20 No.9 Dong Dan San Tiao, Dongcheng District, 21 Beijing 100730, P. R. China 22 Tel/Fax: 86-10-67828516 23 Tel/Fax: 86-10-67828516 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.06.188953; this version posted July 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 24 E-mail: [email protected] 25 26 Dr. Xiaobo Lei 27 No.9 Dong Dan San Tiao, Dongcheng District, 28 Beijing 100730, P. R. China 29 Tel/Fax: 86-10-67828516 30 E-mail: [email protected] 31 32 Dr. Lokesh Sharma 33 TAC S-440, 300 Cedar Street 34 New Haven, CT 06520, USA 35 Tel: (203) 785-3627 36 Fax: 203 785-3826 37 E-mail: [email protected] 38 39 40 41 42 43 44 45 46 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.06.188953; this version posted July 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 47 Abstract 48 COVID-19 pandemic has infected millions of people with mortality exceeding 300,000. There is 49 an urgent need to find therapeutic agents that can help clear the virus to prevent the severe 50 disease and death. Identifying effective and safer drugs can provide with more options to treat 51 the COVID-19 infections either alone or in combination. Here we performed a high throughput 52 screen of approximately 1700 US FDA approved compounds to identify novel therapeutic agents 53 that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step 54 screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral 55 activities. The effective compounds were then screened for their effectiveness in inhibiting 56 SARS-CoV-2. These screens have identified 24 anti-SARS-CoV-2 drugs including previously 57 reported compounds such as hydroxychloroquine, amlodipine, arbidol hydrochloride, tilorone 58 2HCl, dronedarone hydrochloride, and merfloquine hydrochloride. Five of the newly identified 59 drugs had a safety index (cytotoxic/effective concentration) of >600, indicating wide therapeutic 60 window compared to hydroxychloroquine which had safety index of 22 in similar experiments. 61 Mechanistically, five of the effective compounds were found to block SARS-CoV-2 S protein- 62 mediated cell fusion. These FDA approved compounds can provide much needed therapeutic 63 options that we urgently need in the midst of the pandemic. 64 65 66 67 68 69 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.06.188953; this version posted July 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 70 Introduction 71 Novel coronavirus mediated disease (COVID-19) emerged as a major pandemic and has spread 72 across the world in such a short span of time since Dec 2019. As of May 15, 2020, more than 4.5 73 million confirmed infections have been reported with approximately 308,000 deaths (WHO, 74 situation report 116). These numbers may be a vast underestimation as many of the infected 75 patients may remain asymptomatic and can only be detected by antibody testing1. Similarly, 76 many of the deaths may not be accounted due to lack of testing. The disease is caused by a novel 77 coronavirus termed SARS-CoV-2 which belongs to the Coronaviridae family and is the third 78 major coronavirus pandemic in last 20 years after Severe Acute Respiratory Syndrome (SARS) 79 and Middle East Respiratory Syndrome (MERS)2-7. The lack of available therapeutic options is a 80 major limiting factor in treating these infections which leads to excessive mortality. 81 Currently, there is an urgent and unmet need of effective antiviral therapy that can not only 82 decrease the disease burden in the patient but can also decrease the ability of the person to infect 83 others. Developing a novel drug many take years to confirm the safety and efficacy, which may 84 not be practical to deal with a widespread pandemic that is killing thousands of people every day. 85 Alternatively, it sounds a lucrative option to repurpose US Food and Drug Administration (FDA) 86 approved drugs for their efficacy against SARS-CoV-2. Earlier screens have found antiviral 87 efficacy of approved therapies such as hydroxychloroquine8-12, however, these therapies failed to 88 provide any beneficial effects in COVID-19 due to their toxic side effects13-18. Finding efficacy 89 of an approved drug against SARS-CoV-2 with minimal toxicity can provide much needed 90 therapeutic option to treat COVID-19. 91 Here we screened approximately 1700 US FDA approved compounds to test their ability to 92 inhibit SARS-CoV-2 replication. Our data report finds 24 compounds that are highly effective in 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.06.188953; this version posted July 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 93 inhibiting SARS-CoV-2 replication at concentrations that were significantly lower than those 94 having cytotoxic effects. We also investigated possible mechanism of these compounds. 95 Results 96 Inhibitory potential of FDA approved drugs against human coronavirus OC43. Initial 97 screening was performed using HCoV-OC43 due to its low biosafety concerns. OC43 is a human 98 coronavirus that usually causes mild disease in humans and cattle19. The experimental protocol is 99 demonstrated in Fig. 1A using LLC-MK2 cells which were infected with OC43 at a MOI of 1 for 100 48 h in presence of the US FDA licensed compounds. The inhibitory potentials of these 101 compounds were measured with the treatment of compounds at 10 μM for 48 hours. The viral 102 presence was detected by immunostaining for the virus and DAPI staining for the cell nuclei. 103 The inhibitory capacity was measured by using the ratio of viral fluorescence to the DAPI and is 104 depicted in Fig. 1B. The initial screen obtained 231 compounds that had ability to inhibit OC43 105 replication >95%. The remdesivir was used to as a positive control (Fig. 1 C and D). 106 Calculation of IC50, CC50 and SI of FDA approved drugs against OC43. Next, we sought to 107 determine the effective concentrations of positively screened drugs in our initial approach and 108 test the toxicity profile of these drugs in relation to their viral inhibitory concentrations. Our data 109 show that vast majority of the positively screened drugs were effective in inhibiting the viral 110 replication at sub-micromolar concentrations including many of them can almost completely 111 inhibit the viral replication at micromolar range (Fig. 2). Surprisingly, the effective drugs against 112 the coronavirus belonged to a wide range of therapeutic groups including those used for 113 neurological diseases, hormones, enzymes and antimicrobial agents among others (Table 1). The 114 cytotoxic concentration to kill 50% cells (CC50) was noted for these drugs by measuring cell 115 viability over similar concentrations. The selective index in our study was found to be >600 for 5 5 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.06.188953; this version posted July 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 116 of the screened compounds. The SI for the hydroxychloroquine was 22 in our study, indicating 117 increased safety of newly identified drugs compared to the hydroxychloroquine. 118 Testing the antiviral effectiveness of positive drugs against SARS-CoV-2. Finally, we sought 119 to determine whether these compounds can show efficacy against SARS-CoV-2, the causative 120 agent of COVID-19. Positive compounds from the initial screen were tested for their antiviral 121 efficacy against SARS-CoV-2 in Vero cells. SARS-CoV-2 replicates within the Vero cells and 122 causes cytopathic effects in these cells in absence of any antiviral treatment.
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