2. Academic Validation
  3. SARS-CoV-2 papain-like protease (PLpro) inhibitory and antiviral activity of small molecule derivatives for drug leads

SARS-CoV-2 papain-like protease (PLpro) inhibitory and antiviral activity of small molecule derivatives for drug leads

  • Bioorg Med Chem Lett. 2023 Sep 27:96:129489. doi: 10.1016/j.bmcl.2023.129489.
Arun K Ghosh 1,  Dana Shahabi 2,  Mackenzie E C Imhoff 3,  Satish Kovela 2,  Ashish Sharma 2,  Shin-Ichiro Hattori 4,  Nobuyo Higashi-Kuwata 4,  Hiroaki Mitsuya 5,  Andrew D Mesecar 6
Affiliations

Affiliations

  • 1 Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 USA. Electronic address: [email protected].
  • 2 Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 USA.
  • 3 Department of Biochemistry, Purdue University, West Lafayette, IN 47907 USA.
  • 4 Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655 Japan.
  • 5 Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655 Japan; Department of Clinical Sciences, Kumamoto University Hospital, Kumamoto 860-8556 Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute, Bethesda, MD 20892 USA.
  • 6 Department of Biological Sciences, Purdue University, West Lafayette, IN 47907 USA.
PMID: 37770002 DOI: 10.1016/j.bmcl.2023.129489
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.

Keywords

Antiviral; Covid-19; Inhibitor; SARS-CoV-2 protease; Synthesis.

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