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

Bin Tan, Chang Liu, Kan Li, Prakash Jadhav, George Lambrinidis, Lan Zhu, Linda Olson, Haozhou Tan, Yu Wen, Antonios Kolocouris, Wei Liu, Jun Wang

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)14544-14563
Number of pages20
JournalJournal of Medicinal Chemistry
Issue number21
StatePublished - Nov 9 2023
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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