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

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.

 

Comments:

It sounds like you're describing a research study or a scientific paper related to the development of antiviral compounds against Enterovirus D68 (EV-D68). The study focuses on a specific viral protein, 2A protease (2Apro), which is a target for potential antiviral drugs. The researchers investigated the structure of EV-D68 2Apro and its mutant form, C107A, using X-ray crystallography. They also explored the inhibitory effects of telaprevir, a known 2Apro inhibitor, and conducted molecular dynamics simulations to understand its binding with the viral protein.

Based on the insights gained from the X-ray crystal structures and molecular dynamics simulations, the researchers optimized telaprevir's structure by modifying its reactive warhead and certain chemical groups (P1-P4 substitutions). These modifications led to the development of new 2Apro inhibitors with enhanced antiviral activity compared to telaprevir. These newly discovered compounds show promise as potential candidates for further development as antiviral drugs against EV-D68.

Please let me know if you have any specific questions about this research or if there's anything else I can help you with!

Related Products

Cat.No. Product Name Information
S1538 Telaprevir Telaprevir is an HCV NS3-4A serine protease inhibitor with IC50 of 0.35 μM.

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COVID-19 HCV Protease