1区 · 综合性期刊
Article
作者: Arnold, Eddy ; Jadhav, Prakash ; Ruiz, Francesc Xavier ; Tan, Haozhou ; Tan, Bin ; Zhang, Xiaoming ; Ansari, Ahmadullah ; Chopra, Ashima ; Li, Kan ; Ford, Alexandra ; Wang, Jun ; Chi, Xiang ; Deng, Xufang
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.