Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model
成果类型：
Article
署名作者：
Tan, Bin; Zhang, Xiaoming; Ansari, Ahmadullah; Jadhav, Prakash; Tan, Haozhou; Li, Kan; Chopra, Ashima; Ford, Alexandra; Chi, Xiang; Ruiz, Francesc Xavier; Arnold, Eddy; Deng, Xufang; Wang, Jun
署名单位：
Rutgers University System; Rutgers University New Brunswick; Oklahoma State University System; Oklahoma State University - Stillwater; Rutgers University System; Rutgers University New Brunswick; Rutgers University System; Rutgers University New Brunswick; Oklahoma State University System; Oklahoma State University - Stillwater; Oklahoma State University System; Oklahoma State University - Stillwater
刊物名称：
SCIENCE
ISSN/ISSBN：
0036-12875
DOI：
10.1126/science.adm9724
发表日期：
2024-03-29
页码：
1434-1440
关键词：
摘要：
The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PLpro) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PLpro inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PLpro with the inhibitory constant K-i values from 13.2 to 88.2 nanomolar. The co-crystal structures of PLpro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC50 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 PLpro inhibitors are promising oral SARS-CoV-2 antiviral candidates.