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Design of SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model.

ABSTRACT: 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. In this study, we designed and synthesized 85 noncovalent PLpro inhibitors that bind to the newly discovered Val70Ub site and the known BL2 groove pocket. Potent compounds inhibited PLpro with inhibitory constant Ki values from 13.2 to 88.2 nM. 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 μM. Oral treatment with Jun12682 significantly improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting PLpro inhibitors are promising oral SARS-CoV-2 antiviral candidates.

SUBMITTER: Tan B 

PROVIDER: S-EPMC10705561 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Design of SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model.

Tan Bin B   Zhang Xiaoming X   Ansari Ahmadullah A   Jadhav Prakash P   Tan Haozhou H   Li Kan K   Chopra Ashima A   Ford Alexandra A   Chi Xiang X   Ruiz Francesc Xavier FX   Arnold Eddy E   Deng Xufang X   Wang Jun J  

bioRxiv : the preprint server for biology 20231203

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PL<sup>pro</sup>) is a promising but challenging drug target. In this study, we designed and synthesized 85 noncovalent PL<sup>pro</sup> inhibitors that bind to the newly discovered Val70<sup>Ub</sup> site and the known BL2 groove pocket. Potent compounds inhibited PL<sup>pro</sup> with inhibitory constant K<sub>i</sub> values from 13.2 to 88.2 nM. The co-cry  ...[more]

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