Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model
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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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:383 |
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| Enthalten in: |
Science (New York, N.Y.) - 383(2024), 6690 vom: 29. März, Seite 1434-1440 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tan, Bin [VerfasserIn] |
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| Links: |
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| Themen: |
Coronavirus Papain-Like Proteases |
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| Anmerkungen: |
Date Completed 01.04.2024 Date Revised 08.04.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Dec 03;:. - PMID 38076941 Citation Status MEDLINE |
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| doi: |
10.1126/science.adm9724 |
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| funding: |
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NLM370367871 |
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| 520 | |a 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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| 700 | 1 | |a Ansari, Ahmadullah |e verfasserin |4 aut | |
| 700 | 1 | |a Jadhav, Prakash |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Haozhou |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Kan |e verfasserin |4 aut | |
| 700 | 1 | |a Chopra, Ashima |e verfasserin |4 aut | |
| 700 | 1 | |a Ford, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Chi, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Ruiz, Francesc Xavier |e verfasserin |4 aut | |
| 700 | 1 | |a Arnold, Eddy |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Xufang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jun |e verfasserin |4 aut | |
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