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

Bin Tan; Xiaoming Zhang; Ahmadullah Ansari; Prakash Jadhav; Haozhou Tan; Kan Li; Ashima Chopra; Alexandra Ford; Xiang Chi; Francesc Xavier Ruiz; Eddy Arnold; Xufang Deng; Jun Wang

doi:10.1126/science.adm9724

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

Bin Tan, Xiaoming Zhang, Ahmadullah Ansari, Prakash Jadhav, Haozhou Tan, Kan Li, Ashima Chopra, Alexandra Ford, Xiang Chi, Francesc Xavier Ruiz, Eddy Arnold, Xufang Deng, Jun Wang

Center for Advanced Biotechnology and Medicine (CABM)

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

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 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.

Original language	English (US)
Pages (from-to)	1434-1440
Number of pages	7
Journal	Science
Volume	383
Issue number	6690
DOIs	https://doi.org/10.1126/science.adm9724
State	Published - Mar 29 2024

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title = "Design of a 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. 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 Ki 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.",

author = "Bin Tan and Xiaoming Zhang and Ahmadullah Ansari and Prakash Jadhav and Haozhou Tan and Kan Li and Ashima Chopra and Alexandra Ford and Xiang Chi and Ruiz, {Francesc Xavier} and Eddy Arnold and Xufang Deng and Jun Wang",

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month = mar,

day = "29",

doi = "10.1126/science.adm9724",

language = "English (US)",

volume = "383",

pages = "1434--1440",

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T1 - Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model

AU - Tan, Bin

AU - Zhang, Xiaoming

AU - Ansari, Ahmadullah

AU - Jadhav, Prakash

AU - Tan, Haozhou

AU - Li, Kan

AU - Chopra, Ashima

AU - Ford, Alexandra

AU - Chi, Xiang

AU - Ruiz, Francesc Xavier

AU - Arnold, Eddy

AU - Deng, Xufang

AU - Wang, Jun

PY - 2024/3/29

Y1 - 2024/3/29

N2 - 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 Ki 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.

AB - 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 Ki 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.

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EP - 1440

JO - Science

JF - Science

IS - 6690

ER -

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

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