Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening
Abstract Variants of SARS-CoV-2 have continued to emerge across the world and cause hundreds of deaths each week. Due to the limited efficacy of vaccines against SARS-CoV-2 and resistance to current therapies, additional anti-viral therapeutics with pan-coronavirus activity are of high interest. Her...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55421-5 |
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| author | Hengrui Liu Arie Zask Farhad Forouhar Sho Iketani Alana Williams Daniel R. Vaz Dahlya Habashi Karenna Choi Samuel J. Resnick Seo Jung Hong David H. Lovett Tian Bai Alejandro Chavez David D. Ho Brent R. Stockwell |
| author_facet | Hengrui Liu Arie Zask Farhad Forouhar Sho Iketani Alana Williams Daniel R. Vaz Dahlya Habashi Karenna Choi Samuel J. Resnick Seo Jung Hong David H. Lovett Tian Bai Alejandro Chavez David D. Ho Brent R. Stockwell |
| author_sort | Hengrui Liu |
| collection | DOAJ |
| description | Abstract Variants of SARS-CoV-2 have continued to emerge across the world and cause hundreds of deaths each week. Due to the limited efficacy of vaccines against SARS-CoV-2 and resistance to current therapies, additional anti-viral therapeutics with pan-coronavirus activity are of high interest. Here, we screen 2.8 billion compounds from a DNA-encoded chemical library and identify small molecules that are non-covalent inhibitors targeting the conserved 3CL protease of SARS-CoV-2 and other coronaviruses. We perform structure-based optimization, leading to the creation of a series of potent, non-covalent SARS-CoV-2 3CL protease inhibitors, for coronavirus infections. To characterize their binding mechanism to the 3CL protease, we determine 16 co-crystal structures and find that optimized inhibitors specifically interact with both protomers of the native homodimer of 3CL protease. Since 3CL protease is catalytically competent only in the dimeric state, these data provide insight into the design of drug-like inhibitors targeting the native homodimer state. With a binding mode different from the covalent 3CL inhibitor nirmatrelvir, the protease inhibitor in the COVID drug Paxlovid, these compounds may overcome resistance reported for nirmatrelvir and complement its clinical utility. |
| format | Article |
| id | doaj-art-7585a46ba6624df584b8d3d647d792f8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7585a46ba6624df584b8d3d647d792f82025-01-05T12:40:37ZengNature PortfolioNature Communications2041-17232025-01-0116111810.1038/s41467-024-55421-5Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screeningHengrui Liu0Arie Zask1Farhad Forouhar2Sho Iketani3Alana Williams4Daniel R. Vaz5Dahlya Habashi6Karenna Choi7Samuel J. Resnick8Seo Jung Hong9David H. Lovett10Tian Bai11Alejandro Chavez12David D. Ho13Brent R. Stockwell14Department of Chemistry, Columbia UniversityDepartment of Biological Sciences, Columbia UniversityHerbert Irving Comprehensive Cancer Center, Columbia University Irving Medical CenterAaron Diamond AIDS Research Center, Columbia University Irving Medical CenterDepartment of Chemistry, Columbia UniversityDepartment of Chemistry, Columbia UniversityDepartment of Biological Sciences, Columbia UniversityDepartment of Biological Sciences, Columbia UniversityDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Pathology and Cell Biology, Columbia University Irving Medical CenterAaron Diamond AIDS Research Center, Columbia University Irving Medical CenterAaron Diamond AIDS Research Center, Columbia University Irving Medical CenterDepartment of Pediatrics, University of California San DiegoAaron Diamond AIDS Research Center, Columbia University Irving Medical CenterDepartment of Chemistry, Columbia UniversityAbstract Variants of SARS-CoV-2 have continued to emerge across the world and cause hundreds of deaths each week. Due to the limited efficacy of vaccines against SARS-CoV-2 and resistance to current therapies, additional anti-viral therapeutics with pan-coronavirus activity are of high interest. Here, we screen 2.8 billion compounds from a DNA-encoded chemical library and identify small molecules that are non-covalent inhibitors targeting the conserved 3CL protease of SARS-CoV-2 and other coronaviruses. We perform structure-based optimization, leading to the creation of a series of potent, non-covalent SARS-CoV-2 3CL protease inhibitors, for coronavirus infections. To characterize their binding mechanism to the 3CL protease, we determine 16 co-crystal structures and find that optimized inhibitors specifically interact with both protomers of the native homodimer of 3CL protease. Since 3CL protease is catalytically competent only in the dimeric state, these data provide insight into the design of drug-like inhibitors targeting the native homodimer state. With a binding mode different from the covalent 3CL inhibitor nirmatrelvir, the protease inhibitor in the COVID drug Paxlovid, these compounds may overcome resistance reported for nirmatrelvir and complement its clinical utility.https://doi.org/10.1038/s41467-024-55421-5 |
| spellingShingle | Hengrui Liu Arie Zask Farhad Forouhar Sho Iketani Alana Williams Daniel R. Vaz Dahlya Habashi Karenna Choi Samuel J. Resnick Seo Jung Hong David H. Lovett Tian Bai Alejandro Chavez David D. Ho Brent R. Stockwell Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening Nature Communications |
| title | Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening |
| title_full | Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening |
| title_fullStr | Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening |
| title_full_unstemmed | Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening |
| title_short | Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening |
| title_sort | development of small molecule non covalent coronavirus 3cl protease inhibitors from dna encoded chemical library screening |
| url | https://doi.org/10.1038/s41467-024-55421-5 |
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