Identification and Exploration of a Series of SARS-Cov-2 MPro Cyano-Based Inhibitors Revealing Ortho-Substitution Effects within the P3 Biphenyl Group
Year: 2025
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide Starting from a simple scaffold hopping exercise based on our previous exploration of cysteine protease inhibitors against legumain, compound 6a was identified as a starting point for the development of a SARS-CoV-2 main protease (M Pro ) inhibitor. Compound 6a displayed submicromolar biochemical potency in the ultrasensitive assay developed by Drag and co-workers. Through an iterative structure–activity relationship campaign, we discovered an unexpected improvement in both biochemical and cellular potency through the incorporation of an ortho substituent within the P3 benzamide. X-ray crystallography revealed that incorporation of the ortho substituent caused a subtle but important binding enhancement of the P1 glutamate group within the M Pro S1 pocket. While incorporation of the ortho substituent improved the potency, the off-target selectivity against a panel of cysteine proteases and cell activity remained suboptimal. Further scanning of the P2 core revealed that incorporation of the 3.1.0 proline could address these issues and afford compound 22e, a highly potent and cellularly active M Pro inhibitor.
Source: ACS Medicinal Chemistry Letters
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: U.S. Department of Energy, Cancer Prevention and Research Institute of Texas, Department of Education, Northern Ireland, UK Research and Innovation, National Institutes of Health, Office of Science, University of Texas Health Science Center at San Antonio, National Cancer Institute, National Institute of General Medical Sciences, Office of Research Infrastructure Programs, National Institutes of Health, Argonne National Laboratory
Awards: G102163711, G107546177, Mays Cancer Center at UT Health SA, G1313983767, G1386414003, G1664757510, Recruitment of Rising Stars, G2287611682, G262962599, G2849897711, G3075337988, G32573923, G3325152545, G3468900865, G3754226247, G3874765150, G3924411600, G409777406, G4155925329, G4429385918, G498139845, Structural Biology of the Ubiquitin Conjugation System, Pixel Array Detector for Macromolecular Crystallography, G5607048534, G5827286289, Center for Innovative Drug Discovery: Expansion of a Highly Productive Shared Cancer Drug Discovery Resource for Texas, G6292026, G6848031779, G6918803902, G7257490191, G78868261, Upgrade of a Core Laboratory Macromolecular X-ray Diffraction System, G9000051782, Structure and Function of the Essential Cell Cycle Regulator Cdc34, NE-CAT: A Resource for Advanced Macromolecular Crystallography, G969889393, G993149817
OpenAlex ID: W4414495870