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Etoposide targets 2A protease to inhibit enterovirus 71 replication
Qinqin Liang1, Sai Shi2, Qingjie Zhang1
1Frontiers Science Center for Synthetic Biology (Ministry of Education), Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin, China.
Etoposide, a traditional Chinese medicine derivative, effectively inhibits Enterovirus 71 (EV71) replication by targeting the viral 2A protease. This compound shows broad-spectrum activity against multiple EV71 strains with minimal toxicity, making it a promising antiviral candidate.
Area of Science:
- Virology and Drug Discovery
- Traditional Chinese Medicine (TCM) Applications
Background:
- Enterovirus 71 (EV71) is a significant pathogen causing hand, foot, and mouth disease (HFMD) in children, with no specific antiviral drugs currently approved.
- The EV71 2A protease (2Apro) is crucial for viral replication and host cell function, representing a key target for antiviral development.
Purpose of the Study:
- To identify novel EV71 inhibitors using virtual screening of Traditional Chinese Medicine (TCM) compounds and their derivatives.
- To evaluate the antiviral activity and mechanism of action of identified compounds against EV71.
Main Methods:
- Virtual screening of TCM monomers and derivatives against EV71 2Apro.
- In vitro antiviral assays to assess inhibition of EV71 replication in various cell lines.
- Molecular dynamics simulations and site-directed mutagenesis to elucidate the binding mechanism of the inhibitor to EV71 2Apro.
Main Results:
- Etoposide, a derivative of a TCM monomer, was identified as a potent inhibitor of EV71.
- Etoposide demonstrated concentration-dependent inhibition of EV71 (strains A, B, C) and CVA16 replication with low cytotoxicity.
- Etoposide targets EV71 2Apro by binding to residues Y89 and P107, as confirmed by molecular dynamics and mutagenesis studies.
Conclusions:
- Etoposide is a promising broad-spectrum antiviral agent against EV71 and related viruses.
- The study reveals a novel mechanism of EV71 inhibition by targeting the 2Apro protease.
- Etoposide warrants further investigation for clinical development as an anti-EV71 therapeutic.
