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TitleViral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-A71 capsid.
Journal, issue, pagesPLoS Pathog, Vol. 15, Issue 5, Page e1007760, Year 2019
Publish dateMay 9, 2019
AuthorsLiang Sun / Hyunwook Lee / Hendrik Jan Thibaut / Kristina Lanko / Eva Rivero-Buceta / Carol Bator / Belen Martinez-Gualda / Kai Dallmeier / Leen Delang / Pieter Leyssen / Federico Gago / Ana San-Félix / Susan Hafenstein / Carmen Mirabelli / Johan Neyts /
PubMed AbstractEnterovirus 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 ...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.
External linksPLoS Pathog / PubMed:31071193 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 3.59 Å
Structure data

EMDB-7905:
Structure of the EVA71 strain 11316 capsid
Method: EM (single particle) / Resolution: 3.3 Å

7913

6diz

EMDB-7913, PDB-6diz:
EV-A71 strain 11316 complexed with tryptophan dendrimer MADAL_0385
Method: EM (single particle) / Resolution: 3.59 Å

Chemicals

ChemComp-SPH:
SPHINGOSINE

Source
  • enterovirus a71
KeywordsVIRUS / tryptophan dendrimers / EV-A71 / 5-fold vertex / Cryo-EM

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