Small molecules targeting coxsackievirus A16 capsid inactivate viral particles and prevent viral binding

Abstract

Coxsackievirus A16 (CVA16) is an etiologic agent of hand, foot, and mouth disease (HFMD) that affects young children, and although typically self-limited, severe complications, and fatal cases have been reported. Due to the lack of specific medication and vaccines against CVA16, there is currently a need to develop effective antivirals to better control CVA16 infections in epidemic areas. In this study, we identified the tannins chebulagic acid (CHLA) and punicalagin (PUG) as small molecules that can efficiently disrupt the CVA16 infection of human rhabdomyosarcoma cells. Both compounds significantly reduced CVA16 infectivity at micromolar concentrations without apparent cytotoxicity. A mechanistic analysis revealed that the tannins particularly targeted the CVA16 entry phase by inactivating cell-free viral particles and inhibiting viral binding. Further examination by molecular docking analysis pinpointed the targets of the tannins in the fivefold axis canyon region of the CVA16 capsid near the pocket entrance that functions in cell surface receptor binding. We suggest that CHLA and PUG are efficient antagonists of CVA16 entry and could be of value as antiviral candidates or as starting points for developing molecules to treat CVA16 infections.

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Acknowledgements

The authors are grateful to Drs. Shin-Ru Shih, Ta-Chen Lin, and Chih-Hua Tseng for reagents, and Ms. C.-H.L. for help with the manuscript. We also thank Dr. Joshua Beckham at the University of Texas at Austin for critical reading of the manuscript and technical support with molecular docking. This study was supported by funding from the Kaohsiung Medical University Research Foundation (KMU-Q107014 to C.-J.L.) and the Ministry of Science and Technology of Taiwan (MOST107-2320-B-037-002 to C.-J.L. and L.-T.L.; MOST106-2320-B-038-021 to L.-T.L.).

Author contributions

C.-J.L. and L.-T.L. conceived and designed the experiments. C.-J.L., C.-H.L., J.Y.W. and Y.F.L. performed the experiments. L.-T.L. supervised all research. C.-J.L., C.-H.L., J.Y.W., C.-C.L., Y.-F.L., C.D.R., and L.-T.L. analyzed the data. C.-J.L., C.-H.L., J.Y.W. and L.-T.L. wrote and edited the manuscript. All authors contributed reagents/materials/technical support to this study.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Information accompanies this paper at (10.1038/s41426-018-0165-3).

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