Discovery of Fragment-Based Inhibitors of SARS-CoV-2 PL Pro

Journal of Medicinal Chemistry 2026 Open access

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Authors: Qiangqiang Wei, Ashley J. Taylor, Mahesh A. Barmade, Kevin B. Teuscher, Somanath Chowdhury, Chideraa Apakama, Jordan Anderson-Daniels, Zhu Yongqing, D. Schultz, Tyson A. Rietz, Taylor M. South, Mackenzie M. Crow
+8 more Bin Zhao, Kangsa Amporndanai, John Sensintaffar, Jason Phan, Sara Cherry, Mark R. Denison, Taekyu Lee, Stephen W. Fesik
DOI: 10.1021/acs.jmedchem.5c02832
Cited by: 3
References: 27

Abstract

High Resolution Image Download MS PowerPoint Slide SARS-CoV-2 papain-like protease (PL Pro ) plays a key role in viral replication and the host immune response and is a promising target for developing new antiviral treatments. We previously reported a fragment-based screen to identify hits that bind to SARS-CoV-2 PL Pro . Here, we describe the discovery of potent PL Pro inhibitors by optimizing one of these hits via extensive medicinal chemistry guided by multiple X-ray structures of cocomplexes. Lead compound 46 is shown to bind to the S3 and S4 pockets with nanomolar affinity (0.4 μM) and exhibits robust cellular activity and resistance to mutation. This novel class of PL Pro inhibitors can potentially be used as a starting point for the development of inhibitors to combat the emergence of drug-resistant viral strains and future coronavirus outbreaks.

Fields of Study & Subjects

Pharmacological Receptor Mechanisms and Effects Diverse Scientific Research Studies Bioactive Compounds and Antitumor Agents

Publication details

Journal / source
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Volume
69
Issue
2
Pages
1419–1433
Publication date
12 January 2026
Language
EN