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

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 picomola...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590834/
https://www.ncbi.nlm.nih.gov/pubmed/31071193
http://dx.doi.org/10.1371/journal.ppat.1007760
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author 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
author_facet 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
author_sort Sun, Liang
collection PubMed
description 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.
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spelling pubmed-65908342019-07-05 Viral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-A71 capsid 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 PLoS Pathog Research Article 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. Public Library of Science 2019-05-09 /pmc/articles/PMC6590834/ /pubmed/31071193 http://dx.doi.org/10.1371/journal.ppat.1007760 Text en © 2019 Sun et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
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
Viral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-A71 capsid
title Viral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-A71 capsid
title_full Viral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-A71 capsid
title_fullStr Viral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-A71 capsid
title_full_unstemmed Viral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-A71 capsid
title_short Viral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-A71 capsid
title_sort viral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-a71 capsid
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590834/
https://www.ncbi.nlm.nih.gov/pubmed/31071193
http://dx.doi.org/10.1371/journal.ppat.1007760
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