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PLoS Pathog. 2019 May 9;15(5):e1007760. doi: 10.1371/journal.ppat.1007760. eCollection 2019 May.

Viral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-A71 capsid.

Author information

1
KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
2
Department of Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
3
Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM, CSIC), Madrid, Spain.
4
Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Alcalá, Unidad Asociada IQM-CSIC, Madrid, Spain.
5
Department of Medicine, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.

Abstract

Enterovirus A71 (EV-A71) is a non-polio neurotropic enterovirus with pandemic potential. There are no antiviral agents approved to prevent or treat EV-A71 infections. We here report on the molecular mechanism by which a novel class of tryptophan dendrimers inhibits (at low nanomolar to high picomolar concentration) EV-A71 replication in vitro. A lead compound in the series (MADAL385) prevents binding and internalization of the virus but does not, unlike classical capsid binders, stabilize the particle. By means of resistance selection, reverse genetics and cryo-EM, we map the binding region of MADAL385 to the 5-fold vertex of the viral capsid and demonstrate that a single molecule binds to each vertex. By interacting with this region, MADAL385 prevents the interaction of the virus with its cellular receptors PSGL1 and heparan sulfate, thereby blocking the attachment of EV-A71 to the host cells.

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