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Structure-Based Lead Optimization of Enterovirus D68 2A Protease Inhibitors
1Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, United States.
Journal of Medicinal Chemistry
|October 19, 2023
Summary
New antiviral compounds targeting the Enterovirus D68 (EV-D68) 2A protease were developed. Structure-based optimization of telaprevir led to potent inhibitors, offering hope for EV-D68 treatment.
Area of Science:
- Virology
- Drug Discovery
- Structural Biology
Background:
- Enterovirus D68 (EV-D68) causes respiratory illness and severe neurological complications in children.
- No current vaccine or antiviral therapy exists for EV-D68 infections.
- The viral 2A protease (2Apro) is a validated target for antiviral development.
Purpose of the Study:
- To determine the X-ray crystal structures of EV-D68 2Apro.
- To optimize telaprevir as a 2Apro inhibitor through structure-based drug design.
- To discover novel EV-D68 antiviral compounds with enhanced activity.
Main Methods:
- X-ray crystallography was used to determine the structures of wild-type and mutant EV-D68 2Apro.
- Molecular dynamics simulations predicted telaprevir binding pose.
- Structure-based drug design guided optimization of telaprevir analogs.
Main Results:
- X-ray crystal structures of EV-D68 2Apro were obtained.
- A computational model predicted telaprevir binding, informing structural modifications.
- Optimized compounds demonstrated superior antiviral activity against EV-D68 compared to telaprevir.
Conclusions:
- Structure-based optimization of telaprevir yielded potent EV-D68 2Apro inhibitors.
- These novel compounds show promise as lead candidates for EV-D68 antiviral therapy.
- Further development of these inhibitors could lead to effective treatments for EV-D68.
