posted on 2023-10-19, 22:41authored byBin Tan, Chang Liu, Kan Li, Prakash Jadhav, George Lambrinidis, Lan Zhu, Linda Olson, Haozhou Tan, Yu Wen, Antonios Kolocouris, Wei Liu, Jun Wang
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.