A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

Abstract

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 . 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 FDAapproved 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.

An OpenData portal to share COVID-19 drug repurposing data in real time

“…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.…”

Simeprevir potently suppresses SARS-CoV-2 replication and synergizes with remdesivir

“…Two complementary approaches have been adopted to identify novel drugs or compounds that can suppress SARS-CoV-2 replication. One approach relies on in vitro profiling of the antiviral efficacy of up to thousands of compounds in early clinical development, or drugs already approved by the U.S. Food and Drug Administration (FDA) (18)(19)(20)(21)(22). On the other hand, as the crystal structure of the M pro (23,24), papain-like protease (PL pro ) (25) and the cryo-EM structure of the nsp12-nsp7-nsp8 RdRP complex (11,26) of the SARS-CoV-2 virus became available, the structurebased development of their specific inhibitors becomes feasible.…”

Discovery of Synergistic and Antagonistic Drug Combinations against SARS-CoV-2 In Vitro

“…These include numerous research groups evaluating compounds in enzymatic and cellular assays to determine antiviral activity. [14][15][16][17][18][19][20][21][22][23] Comparatively, there has been limited systematic screening of drug combinations. 24 Meanwhile, the situation in clinical trials is somewhat different.…”

“…27 As of June 27, 2020, no combination therapy has yet yielded positive results in Phase III randomized clinical trials. 28 While there are many ongoing or upcoming clinical trials testing combinations to treat COVID- 19, few have undergone extensive preclinical studies prior to their combination in patients. Due to a lack of such studies, more information is needed on the combinatorial use of antivirals and other drugs against SARS-CoV-2 in order to (1) more efficiently prioritize synergistic combinations for translation into clinical use; and (2) flag antagonistic combinations prior to their evaluation in the preclinical stage.…”