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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Capsid / drug effects
  • Capsid / metabolism*
  • Capsid Proteins / chemistry
  • Capsid Proteins / metabolism
  • Dendrimers / chemistry
  • Dendrimers / pharmacology
  • Enterovirus / drug effects*
  • Enterovirus Infections / drug therapy
  • Enterovirus Infections / metabolism*
  • Enterovirus Infections / virology
  • HeLa Cells
  • Heparitin Sulfate / antagonists & inhibitors
  • Heparitin Sulfate / metabolism*
  • Humans
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / metabolism*
  • Protein Conformation
  • Tryptophan / chemistry
  • Tryptophan / pharmacology*
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Capsid Proteins
  • Dendrimers
  • Membrane Glycoproteins
  • P-selectin ligand protein
  • VP1 protein, enterovirus B
  • Tryptophan
  • Heparitin Sulfate

Grant support

LS, KL, LD, PL, CM and JN received funding of Belgian Interuniversity Attraction Poles (IAP) Phase VII–P7/45 (BELVIR) and the EU FP7 Industry-Academia Partnerships and Pathways Project AIROPICO. LS received funding of China Scholarship Council (CSC) (Grant 201403250056). HL, CB and SH received a grant with the Pennsylvania Department of Health using Tobacco CURE Funds. ERB, BMG and ASF received the grant “Ministerio de Economia, Industriay Competitividad, Gobierno de España” and “European Regional Development Funds” projects number SAF2015-64629-C2-1-R (MINECO/FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.