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

• Published in: Bioorganic & Medicinal Chemistry Letters Vol. 96; p. 129489
• Main Authors: Ghosh, Arun K., Shahabi, Dana, Imhoff, Mackenzie E.C., Kovela, Satish, Sharma, Ashish, Hattori, Shin-ichiro, Higashi-Kuwata, Nobuyo, Mitsuya, Hiroaki, Mesecar, Andrew D.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.11.2023; Elsevier BV
• Subjects: Antiviral; Antiviral Agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; COVID-19; Humans; Inhibitor; SARS-CoV-2; SARS-CoV-2 protease; Sulfonamides; Sulfonamides - pharmacology; Synthesis; Antiviral; SARS-CoV-2 protease; Inhibitor; Synthesis; Covid-19
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2023.129489

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.