Ginkgolic acid and anacardic acid are specific covalent inhibitors of SARS-CoV-2 cysteine proteases
Zinuo Chen, Qinghua Cui, Laura Cooper, Pin Zhang, Hyun Lee, Zhaoyu Chen, Yanyan Wang, Xiaoyun Liu, Lijun Rong, Ruikun Du
Abstract
Abstract Background In the urgent campaign to develop therapeutics against SARS-CoV-2, natural products have been an important source of new lead compounds. Results We herein identified two natural products, ginkgolic acid and anacardic acid, as inhibitors using a high-throughput screen targeting the SARS-CoV-2 papain-like protease (PL pro ). Moreover, our study demonstrated that the two hit compounds are dual inhibitors targeting the SARS-CoV-2 3-chymotrypsin-like protease (3CL pro ) in addition to PL pro . A mechanism of action study using enzyme kinetics further characterized the two compounds as irreversible inhibitors against both 3CL pro and PL pro . Significantly, both identified compounds inhibit SARS-CoV-2 replication in vitro at nontoxic concentrations. Conclusions Our finding provides two novel natural products as promising SARS-CoV-2 antivirals.