Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs

Abstract

27Drug repositioning is the only feasible option to address the COVID-19 global challenge 28 immediately. We screened a panel of 48 FDA-approved drugs against SARS-CoV-2 which were 29 pre-selected by an assay of SARS-CoV and identified 24 potential antiviral drug candidates 30 against SARS-CoV-2 infection. Some drug candidates showed very low micromolar IC50s and 31 in particular, two FDA-approved drugs -niclosamide and ciclesonidewere notable in some 32 respects. 33 on June 9, 2020 by guest http://aac.asm.org/ Downloaded from 34 COVID-19 is an emerging infectious disease caused by a novel coronavirus, SARS-CoV-2 (1). 35Although the case fatality rate due to this viral infection varies from 1 to 12% (2), the 36 transmission rate is relatively high (3) and recently, the WHO declared COVID-19 outbreak a 37 pandemic. Currently, there is no vaccines or therapeutics available and the patients with COVID-38 19 are being treated with supportive care. 39Drug repositioning could be an effective strategy to respond immediately to emerging infectious 40 diseases since the new drug development usually takes more than 10 years (4). FDA-approved 41 drugs provide safe alternatives only in the case where at least modest antiviral activity can be 42 achieved. Accordingly, several drugs are being tested in numerous clinical trials (5) including 43 remdesivir, lopinavir, and chloroquine (6). 44In this study, we screened a panel of FDA-approved drugs to identify antiviral drug candidates 45 for the treatment of COVID-19 and suggest the identified drug candidates may be considered for 46 therapeutic development. 48 Results and Discussion 49We screened approximately 3,000 FDA-and IND-approved drug library against SARS-CoV to 50 identify antiviral drug candidates (manuscript in preparation). Since the SARS-CoV and SARS-51 CoV-2 are very similar (79.5% sequence identity) (1), the drugs which show antiviral activity 52 against SARS-CoV are expected to show similar extent of antiviral activity against SARS-CoV-2. 53A total of 35 drugs were selected from the earlier SARS-CoV screening results. In addition, 13 54 drugs were included based on recommendations from infectious diseases specialists (Table 1). 55For screening experiments, Vero cells were used and each drug was added to the cells prior to 56 the virus infection. At 24 h after the infection, the infected cells were scored by 57 immunofluorescence analysis with an antibody specific for the viral N protein of SARS-CoV-2. 58The confocal microscope images of both viral N protein and cell nuclei were analyzed using our 59 in-house Image Mining (IM) software and the dose-response curve (DRC) for each drug was 60 generated (Figure 1). 61 on June 9, 2020 by guest http://aac.asm.org/ Downloaded from Chloroquine, lopinavir, and remdesivir were used as reference drugs with IC 50 values of 9.12, 62 7.28, and 11.41 µM, respectively ( Figure 1A). Among the 48 drugs that were evaluated in our 63 study, 24 drugs showed potential antiviral activities against SARS-CoV-2 with IC 50 values in 64 be...

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“…As a result, the induction of autophagy attenuated the replication of this virus. 60 Interestingly, the anti-helminthic and FDA-approved drug niclosamide has recently been proposed as a potential anti-SARS-CoV-2 agent, 61,62 possibly through its autophagic induction mechanism. 63 It has yet to be elucidated whether panduratin A suppresses SARS-CoV-2 infection via the induction of autophagy, and which pathway is a direct target for this compound.…”

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“…These drugs, and others that have entered clinical trials, were prioritized based on clinical observations or a contemporary understanding of SARS-CoV-2 biology. In addition, numerous drug repurposing efforts have been undertaken, screening both approved and experimental agents [2][3][4][5][6][7][8][9][10] . Yet many published reports solely focus on active hits, and do not disclose the majority (usually >95%) of tested compounds that were inactiveinformation that is critical for understanding and validating disease and drug mechanism-of-action, and for nominating repurposed and novel clinical lead candidates.…”

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“…Results from trials show that ML can predict effective drug candidates against SARS-CoV-2. Meanwhile, drug repositioning is a possible solution for combating the global coronavirus crisis [100]. A panel of 49 FDA-approved drugs that have been selected by an assay of SARS-CoV is monitored to recognize the potential drug candidates against COVID-19 infection.…”