Structure-Based Lead Optimization of Enterovirus D68 2A Protease Inhibitors

  • J Med Chem. 2023 Nov 9;66(21):14544-14563. doi: 10.1021/acs.jmedchem.3c00995.
Bin Tan  1 ,  Chang Liu  2 ,  Kan Li  1 ,  Prakash Jadhav  1 ,  George Lambrinidis  3 ,  Lan Zhu  4 ,  Linda Olson  4 ,  Haozhou Tan  1 ,  Yu Wen  1 ,  Antonios Kolocouris  3 ,  Wei Liu  4 ,  Jun Wang  1
Affiliations
  • 1. Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, United States.
  • 2. School of Molecular Sciences and Biodesign Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287, United States.
  • 3. Laboratory of Medicinal Chemistry, Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771 Athens, Greece.
  • 4. Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
PMID: 37857371 DOI: 10.1021/acs.jmedchem.3c00995
Abstract

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.