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

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 (2A^pro) as a viable antiviral drug target and identified telaprevir as a 2A^pro inhibitor. 2A^pro 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 2A^pro, 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 2A^pro 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 2A^pro inhibitors with improved antiviral activity than telaprevir. These compounds represent promising lead compounds for further development as EV-D68 antivirals.

Journal of Medicinal Chemistry

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

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

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 mol. 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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Indication	Highest Phase	Country/Location	Organization	Date
Enterovirus Infections	Preclinical	United States	Medical College of Wisconsin	19 Oct 2023

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