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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 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 PL^pro inhibitors are promising oral SARS-CoV-2 antiviral candidates.