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

被引：22

作者：

Sun, Liang ^{[1
]}

Lee, Hyunwook ^{[2
]}

Thibaut, Hendrik Jan ^{[1
]}

Lanko, Kristina ^{[1
]}

Rivero-Buceta, Eva ^{[3
]}

Bator, Carol ^{[2
]}

Martinez-Gualda, Belen ^{[3
]}

Dallmeier, Kai ^{[1
]}

Delang, Leen ^{[1
]}

Leyssen, Pieter ^{[1
]}

Gago, Federico ^{[4
]}

San-Felix, Ana ^{[3
]}

Hafenstein, Susan ^{[2
,5
]}

Mirabelli, Carmen ^{[1
]}

Neyts, Johan ^{[1
]}

机构：

[1] Univ Leuven, KU Leuven, Dept Microbiol & Immunol, Rega Inst Med Res,Lab Virol & Chemotherapy, Leuven, Belgium

[2] Penn State Univ, Dept Biochem & Mol Biol, Huck Inst Life Sci, University Pk, PA 16802 USA

[3] CSIC, IQM, Madrid, Spain

[4] Univ Alcala, Dept Biomed Sci, Sch Med & Hlth Sci, Unidad Asociada IQM CSIC, Madrid, Spain

[5] Penn State Univ, Dept Med, Coll Med, Hershey, PA 16802 USA

来源：

PLOS PATHOGENS | 2019年 / 15卷 / 05期

关键词：

INHIBIT HIV REPLICATION; CLINICAL-FEATURES; 71; INFECTION; RECEPTOR; ATTACHMENT; SEROEPIDEMIOLOGY; CHILDREN; BINDING; VIRUS; AMBER;

D O I：

10.1371/journal.ppat.1007760

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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 (co-) receptors PSGL1 and heparan sulfate, thereby blocking the attachment of EV-A71 to the host cells.

引用

页数：20