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

• DOI: 10.1371/journal.ppat.1007760
• Publication Date: 2019-05-09T17:47:24Z
• Authors: Liang Sun; Hyunwook Lee; Hendrik Jan Thibaut; Kristina Lanko; Eva Rivero-Buceta; Carol Bator; Belen Martinez-Gu...; Kai Dallmeier; Leen Delang; Pieter Leyssen; Federico Gago; Ana San-Félix; Susan Hafenstein; Carmen Mirabelli; Johan Neyts
• Keywords: Internalization

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 novel class of tryptophan dendrimers inhibits (at low nanomolar high picomolar concentration) replication in vitro. A lead compound series (MADAL385) prevents binding and internalization virus but does not, unlike classical capsid binders, stabilize particle. By means resistance selection, reverse genetics cryo-EM, we map region MADAL385 5-fold vertex viral demonstrate that single molecule binds each vertex. interacting this region, interaction its cellular receptors PSGL1 heparan sulfate, thereby blocking attachment host cells.