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

• Published in: PLoS pathogens 2019-05, Vol.15 (5), p.e1007760-e1007760
• Main Authors: Sun, Liang, Lee, Hyunwook, Thibaut, Hendrik Jan, Lanko, Kristina, Rivero-Buceta, Eva, Bator, Carol, Martinez-Gualda, Belen, Dallmeier, Kai, Delang, Leen, Leyssen, Pieter, Gago, Federico, San-Félix, Ana, Hafenstein, Susan, Mirabelli, Carmen, Neyts, Johan
• Format: Article
• Language: English
• Subjects: Amino acids; Anticoagulants; Antimicrobial agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binders; Binding; Biochemistry; Biology and Life Sciences; Capsid - drug effects; Capsid - metabolism; Capsid Proteins - chemistry; Capsid Proteins - metabolism; Cell receptors; Chemotherapy; Dendrimers; Dendrimers - chemistry; Dendrimers - pharmacology; Enterovirus - drug effects; Enterovirus Infections - drug therapy; Enterovirus Infections - metabolism; Enterovirus Infections - virology; Enteroviruses; Epidemics; Funding; Gene expression; Genetics; HeLa Cells; Heparan sulfate; Heparitin Sulfate - antagonists & inhibitors; Heparitin Sulfate - metabolism; Humans; Immunology; Infection; Infections; Internalization; Laboratories; Lead compounds; Life sciences; Medical research; Medicine and Health Sciences; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - metabolism; Molecular biology; Pandemics; Physical Sciences; Pleconaril; Poliomyelitis; Protein Conformation; Proteins; Receptors; Research and Analysis Methods; Software; Sulfates; Supervision; Suramin; Tryptophan; Tryptophan - chemistry; Tryptophan - pharmacology; Virology; Virus Replication - drug effects; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007760

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.