SARS-CoV-2 papain-like protease (PLpro) inhibitory and antiviral activity of small molecule derivatives for drug leads
We report here the synthesis and biological evaluation of a series of small molecule SARS-CoV-2 PLpro inhibitors. We compared the activity of selected compounds in both SARS-CoV-1 and SARS-CoV-2 PLpro inhibitory and antiviral assays. We have synthesized and evaluated several new structural variants...
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| Published in | Bioorganic & Medicinal Chemistry Letters Vol. 96; p. 129489 |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Elsevier Ltd
15.11.2023
Elsevier BV |
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| Online Access | Get full text |
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| Abstract | We report here the synthesis and biological evaluation of a series of small molecule SARS-CoV-2 PLpro inhibitors. We compared the activity of selected compounds in both SARS-CoV-1 and SARS-CoV-2 PLpro inhibitory and antiviral assays. We have synthesized and evaluated several new structural variants of previous leads against SARS-CoV-2 PLpro. The replacement of the carboxamide functionality with sulfonamide derivatives resulted in PLpro inhibitors with potent PLpro inhibitory and antiviral activity in VeroE6 cells similar to GRL0617. To obtain molecular insight, we created an optimized model of a potent sulfonamide derivative in the SARS-CoV-2 PLpro active site. |
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| AbstractList | We report here the synthesis and biological evaluation of a series of small molecule SARS-CoV-2 PLpro inhibitors. We compared the activity of selected compounds in both SARS-CoV-1 and SARS-CoV-2 PLpro inhibitory and antiviral assays. We have synthesized and evaluated several new structural variants of previous leads against SARS-CoV-2 PLpro. The replacement of the carboxamide functionality with sulfonamide derivatives resulted in PLpro inhibitors with potent PLpro inhibitory and antiviral activity in VeroE6 cells similar to GRL0617. To obtain molecular insight, we created an optimized model of a potent sulfonamide derivative in the SARS-CoV-2 PLpro active site. We report here the synthesis and biological evaluation of a series of small molecule SARS-CoV-2 PLpro inhibitors. We compared the activity of selected compounds in both SARS-CoV-1 and SARS-CoV-2 PLpro inhibitory and antiviral assays. We have synthesized and evaluated several new structural variants of previous leads against SARS-CoV-2 PLpro. The replacement of the carboxamide functionality with sulfonamide derivatives resulted in PLpro inhibitors with potent PLpro inhibitory and antiviral activity in VeroE6 cells similar to GRL0617. To obtain molecular insight, we created an optimized model of a potent sulfonamide derivative in the SARS-CoV-2 PLpro active site.We report here the synthesis and biological evaluation of a series of small molecule SARS-CoV-2 PLpro inhibitors. We compared the activity of selected compounds in both SARS-CoV-1 and SARS-CoV-2 PLpro inhibitory and antiviral assays. We have synthesized and evaluated several new structural variants of previous leads against SARS-CoV-2 PLpro. The replacement of the carboxamide functionality with sulfonamide derivatives resulted in PLpro inhibitors with potent PLpro inhibitory and antiviral activity in VeroE6 cells similar to GRL0617. To obtain molecular insight, we created an optimized model of a potent sulfonamide derivative in the SARS-CoV-2 PLpro active site. |
| ArticleNumber | 129489 |
| Author | Mesecar, Andrew D. Higashi-Kuwata, Nobuyo Imhoff, Mackenzie E.C. Shahabi, Dana Mitsuya, Hiroaki Ghosh, Arun K. Hattori, Shin-ichiro Kovela, Satish Sharma, Ashish |
| AuthorAffiliation | b Department of Biochemistry, Purdue University, West Lafayette, IN 47907 (USA) a Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 (USA) f Department of Biological Sciences, Purdue University, West Lafayette, IN 47907 (USA) d Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556 (Japan) e Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute, Bethesda, MD 20892 (USA) c Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655 (Japan) |
| AuthorAffiliation_xml | – name: a Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 (USA) – name: c Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655 (Japan) – name: e Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute, Bethesda, MD 20892 (USA) – name: b Department of Biochemistry, Purdue University, West Lafayette, IN 47907 (USA) – name: d Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556 (Japan) – name: f Department of Biological Sciences, Purdue University, West Lafayette, IN 47907 (USA) |
| Author_xml | – sequence: 1 givenname: Arun K. orcidid: 0000-0003-2472-1841 surname: Ghosh fullname: Ghosh, Arun K. email: akghosh@purdue.edu organization: Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 USA – sequence: 2 givenname: Dana surname: Shahabi fullname: Shahabi, Dana organization: Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 USA – sequence: 3 givenname: Mackenzie E.C. surname: Imhoff fullname: Imhoff, Mackenzie E.C. organization: Department of Biochemistry, Purdue University, West Lafayette, IN 47907 USA – sequence: 4 givenname: Satish surname: Kovela fullname: Kovela, Satish organization: Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 USA – sequence: 5 givenname: Ashish surname: Sharma fullname: Sharma, Ashish organization: Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 USA – sequence: 6 givenname: Shin-ichiro orcidid: 0000-0002-5637-3397 surname: Hattori fullname: Hattori, Shin-ichiro organization: Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655 Japan – sequence: 7 givenname: Nobuyo surname: Higashi-Kuwata fullname: Higashi-Kuwata, Nobuyo organization: Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655 Japan – sequence: 8 givenname: Hiroaki surname: Mitsuya fullname: Mitsuya, Hiroaki organization: Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655 Japan – sequence: 9 givenname: Andrew D. surname: Mesecar fullname: Mesecar, Andrew D. organization: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907 USA |
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| SubjectTerms | Antiviral Antiviral Agents Antiviral Agents - chemistry Antiviral Agents - pharmacology COVID-19 Humans Inhibitor SARS-CoV-2 SARS-CoV-2 protease Sulfonamides Sulfonamides - pharmacology Synthesis |
| Title | SARS-CoV-2 papain-like protease (PLpro) inhibitory and antiviral activity of small molecule derivatives for drug leads |
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