Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model
Bin Tan, Xiaoming Zhang, Ahmadullah Ansari, Prakash D. Jadhav, Haozhou Tan, Kan Li, Ashima Chopra, Alexandra Ford, Xiang Chi, Francesc X. Ruiz, Eddy Arnold, Xufang Deng, Jun Wang
Abstract
The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PL pro ) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PL pro inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PL pro with the inhibitory constant K i values from 13.2 to 88.2 nanomolar. The co-crystal structures of PL pro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC 50 from 0.44 to 2.02 micromolar. Oral treatment with Jun12682 improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting that PL pro inhibitors are promising oral SARS-CoV-2 antiviral candidates.