TY - JOUR
T1 - Structure-Based Lead Optimization of Enterovirus D68 2A Protease Inhibitors
AU - Tan, Bin
AU - Liu, Chang
AU - Li, Kan
AU - Jadhav, Prakash
AU - Lambrinidis, George
AU - Zhu, Lan
AU - Olson, Linda
AU - Tan, Haozhou
AU - Wen, Yu
AU - Kolocouris, Antonios
AU - Liu, Wei
AU - Wang, Jun
N1 - Publisher Copyright:
© 2023 American Chemical Society
PY - 2023/11/9
Y1 - 2023/11/9
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.3c00995
DO - 10.1021/acs.jmedchem.3c00995
M3 - Article
C2 - 37857371
AN - SCOPUS:85176509223
SN - 0022-2623
VL - 66
SP - 14544
EP - 14563
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -