Open AccessIdentification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-Throughput Screening
Author(s) -
Wei Zhu,
Miao Xu,
Catherine Z. Chen,
Hui Guo,
Min Shen,
Xin Hu,
Paul Shinn,
Carleen KlumppThomas,
Samuel G. Michael,
Wei Zheng
Publication year - 2020
Publication title -
acs pharmacology and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.271
H-Index - 10
ISSN - 2575-9108
DOI - 10.1021/acsptsci.0c00108
Subject(s) - drug repositioning , ic50 , protease , pharmacology , covid-19 , coronavirus , drug , virology , chemistry , drug discovery , proteases , medicine , enzyme , in vitro , biochemistry , disease , infectious disease (medical specialty)
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emphasized the urgency to develop effective therapeutics. Drug repurposing screening is regarded as one of the most practical and rapid approaches for the discovery of such therapeutics. The 3C-like protease (3CL pro ), or main protease (M pro ) of SARS-CoV-2 is a valid drug target as it is a specific viral enzyme and plays an essential role in viral replication. We performed a quantitative high-throughput screening (qHTS) of 10 755 compounds consisting of approved and investigational drugs, and bioactive compounds using a SARS-CoV-2 3CL pro assay. Twenty-three small molecule inhibitors of SARS-CoV-2 3CL pro have been identified with IC 50 s ranging from 0.26 to 28.85 μM. Walrycin B (IC 50 = 0.26 μM), hydroxocobalamin (IC 50 = 3.29 μM), suramin sodium (IC 50 = 6.5 μM), Z-DEVD-FMK (IC 50 = 6.81 μM), LLL-12 (IC 50 = 9.84 μM), and Z-FA-FMK (IC 50 = 11.39 μM) are the most potent 3CL pro inhibitors. The activity of the anti-SARS-CoV-2 viral infection was confirmed in 7 of 23 compounds using a SARS-CoV-2 cytopathic effect assay. The results demonstrated a set of SARS-CoV-2 3CL pro inhibitors that may have potential for further clinical evaluation as part of drug combination therapies to treating COVID-19 patients and as starting points for chemistry optimization for new drug development.