Structure-Based Lead Optimization of Enterovirus D68 2A Protease Inhibitors. J Med Chem 2023 Nov 09;66(21):14544-14563
Date
10/20/2023Pubmed ID
37857371Pubmed Central ID
PMC11457037DOI
10.1021/acs.jmedchem.3c00995Scopus ID
2-s2.0-85176509223 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
Enterovirus D68 (EV-D68) virus is a nonpolio enterovirus that typically causes respiratory illness and, in severe cases, can lead to paralysis and death in children. There is currently no vaccine or antiviral for EV-D68. We previously discovered the viral 2A protease (2Apro) as a viable antiviral drug target and identified telaprevir as a 2Apro inhibitor. 2Apro is a viral cysteine protease that cleaves the viral VP1-2A polyprotein junction. In this study, we report the X-ray crystal structures of EV-D68 2Apro, wild-type, and the C107A mutant and the structure-based lead optimization of telaprevir. Guided by the X-ray crystal structure, we predicted the binding pose of telaprevir in 2Apro using molecular dynamics simulations. We then utilized this model to inform structure-based optimization of the telaprevir's reactive warhead and P1-P4 substitutions. These efforts led to the discovery of 2Apro inhibitors with improved antiviral activity than telaprevir. These compounds represent promising lead compounds for further development as EV-D68 antivirals.
Author List
Tan B, Liu C, Li K, Jadhav P, Lambrinidis G, Zhu L, Olson L, Tan H, Wen Y, Kolocouris A, Liu W, Wang JAuthors
Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinLinda J. Olson PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Antiviral AgentsChild
Enterovirus
Enterovirus D, Human
Enterovirus Infections
Humans
Protease Inhibitors
