Related Experiment Video
Updated: May 15, 2025
10:40
Analysis of Group IV Viral SSHHPS Using In Vitro and In Silico Methods
Published on: December 21, 2019
25.9K
Dynamic Cap-Mediated Substrate Access and Potent Inhibitor Design of Monkeypox Virus I7L Protease
Haixia Su1,2, Guoqing Wu3,4, Muya Xiong5
1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 7, 2025
Summary
Researchers elucidated the structure and function of the Monkeypox virus (MPXV) I7L protease, a key target for antiviral drugs. This led to the development of potent covalent inhibitors for potential MPXV therapeutics.
Area of Science:
- Virology
- Structural Biology
- Drug Discovery
Background:
- Monkeypox virus (MPXV) is a global health concern.
- The MPXV I7L protease is crucial for viral replication and a potential drug target.
Purpose of the Study:
- To determine the crystal structure of MPXV I7L protease.
- To understand its substrate recognition, catalytic mechanism, and dynamics.
- To rationally design and discover novel inhibitors.
Main Methods:
- X-ray crystallography
- Molecular dynamics simulations
- AlphaFold3 prediction
- Fluorescence resonance energy transfer (FRET) assay
Main Results:
- First crystal structure of MPXV I7L protease revealed a unique dimeric form and flexible cap region.
- The cap region acts as a conformational switch regulating substrate access.
- Structural insights enabled the design of covalent peptidomimetic inhibitors with nanomolar potency.
Conclusions:
- Comprehensive understanding of MPXV I7L protease structure, dynamics, and function.
- Successful rational design of first-in-class covalent inhibitors.
- Provides a foundation for developing MPXV antiviral drugs.
