Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery

The influenza virus glycoprotein hemagglutinin (HA) participates in critical steps of the attachment of viral particles to the host cell membrane receptor and membrane fusion. Due to its crucial involvement in the initial phases of influenza A infections, HA emerges as a promising target in the sear...

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Autores: Hermoso-Pinilla, Francisco Javier, Valdivia, Aitor, Camarasa Rius, María José, Ginex, Tiziana, Luque, Francisco Javier
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:dnet:digitalcsic_::9f2588d7e279bfdbe9dce78193207961
Acceso en línea:http://hdl.handle.net/10261/428978
Access Level:acceso abierto
Palabra clave:Influenza A virus
Hemagglutinin
Fusion inhibitors
Drug design
Targeted protein degradation
Antiviral proteolysis targeting chimeras
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dc.title.none.fl_str_mv Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery
title Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery
spellingShingle Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery
Hermoso-Pinilla, Francisco Javier
Influenza A virus
Hemagglutinin
Fusion inhibitors
Drug design
Targeted protein degradation
Antiviral proteolysis targeting chimeras
title_short Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery
title_full Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery
title_fullStr Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery
title_full_unstemmed Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery
title_sort Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery
dc.creator.none.fl_str_mv Hermoso-Pinilla, Francisco Javier
Valdivia, Aitor
Camarasa Rius, María José
Ginex, Tiziana
Luque, Francisco Javier
author Hermoso-Pinilla, Francisco Javier
author_facet Hermoso-Pinilla, Francisco Javier
Valdivia, Aitor
Camarasa Rius, María José
Ginex, Tiziana
Luque, Francisco Javier
author_role author
author2 Valdivia, Aitor
Camarasa Rius, María José
Ginex, Tiziana
Luque, Francisco Javier
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
European Commission
Generalitat de Catalunya
Agencia Estatal de Investigación (España)
Consejo Superior de Investigaciones Científicas (España)
Camarasa Rius, María José [0000-0002-4978-6468]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Influenza A virus
Hemagglutinin
Fusion inhibitors
Drug design
Targeted protein degradation
Antiviral proteolysis targeting chimeras
topic Influenza A virus
Hemagglutinin
Fusion inhibitors
Drug design
Targeted protein degradation
Antiviral proteolysis targeting chimeras
description The influenza virus glycoprotein hemagglutinin (HA) participates in critical steps of the attachment of viral particles to the host cell membrane receptor and membrane fusion. Due to its crucial involvement in the initial phases of influenza A infections, HA emerges as a promising target in the search of novel drug-like candidates. Given its pivotal role in the early stages of influenza A infections, intense drug discovery efforts have been undertaken to target HA in the past decades. Drug discovery studies mainly rely on preventing the recognition of sialic acid units by the receptor binding site in the globular head (GH) domain, or the conformational rearrangement required for the fusion of viral and cell membranes. In this work, the aim is to summarize the progress made in HA-targeted development of small molecule fusion inhibitors. To this end, attention will primarily be focused on the analysis of the X-ray crystallographic structures of HA bound to fusion inhibitors. Furthermore, this study also aims to highlight the efforts made in exploiting the structural information in conjunction with molecular modeling techniques to discern the mechanism of action of the fusion inhibitors and to assist the design and interpretation of structure-activity relationships of novel lead compounds will be highlighted. The final section will be dedicated to elucidating novel and promising antiviral strategies proceeding from the transformation of known small molecule antivirals in proteolysis targeting chimera (PROTAC)-based targeted protein degradation. This knowledge will be valuable to assist the exploitation of classical and novel antiviral structure-based strategies, together with a deeper understanding of the mechanism of action and minimization of the impact of drug resistance.
publishDate 2024
dc.date.none.fl_str_mv 2024
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/428978
url http://hdl.handle.net/10261/428978
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136307OB-C21
info:eu-repo/grantAgreement/AEI/PRE2021-100418/
https://doi.org/10.37349/eds.2024.00037
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publisher.none.fl_str_mv Open Exploration
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instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
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spelling Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discoveryHermoso-Pinilla, Francisco JavierValdivia, AitorCamarasa Rius, María JoséGinex, TizianaLuque, Francisco JavierInfluenza A virusHemagglutininFusion inhibitorsDrug designTargeted protein degradationAntiviral proteolysis targeting chimerasThe influenza virus glycoprotein hemagglutinin (HA) participates in critical steps of the attachment of viral particles to the host cell membrane receptor and membrane fusion. Due to its crucial involvement in the initial phases of influenza A infections, HA emerges as a promising target in the search of novel drug-like candidates. Given its pivotal role in the early stages of influenza A infections, intense drug discovery efforts have been undertaken to target HA in the past decades. Drug discovery studies mainly rely on preventing the recognition of sialic acid units by the receptor binding site in the globular head (GH) domain, or the conformational rearrangement required for the fusion of viral and cell membranes. In this work, the aim is to summarize the progress made in HA-targeted development of small molecule fusion inhibitors. To this end, attention will primarily be focused on the analysis of the X-ray crystallographic structures of HA bound to fusion inhibitors. Furthermore, this study also aims to highlight the efforts made in exploiting the structural information in conjunction with molecular modeling techniques to discern the mechanism of action of the fusion inhibitors and to assist the design and interpretation of structure-activity relationships of novel lead compounds will be highlighted. The final section will be dedicated to elucidating novel and promising antiviral strategies proceeding from the transformation of known small molecule antivirals in proteolysis targeting chimera (PROTAC)-based targeted protein degradation. This knowledge will be valuable to assist the exploitation of classical and novel antiviral structure-based strategies, together with a deeper understanding of the mechanism of action and minimization of the impact of drug resistance.The research was given financial support by the Spanish Ministerio de Ciencia e Innovación [PID2020117646RB-I00 MCIN/AEI/10.13039/501100011033, PID2019-104070-RB-C21]; the Spanish Ministerio de Ciencia, Innovación y Universidades [PID2022-136307OB-C21/AEI/10.13039/501100011033/FEDER, UE]; Maria de Maetzu [CEX2021-001202-M]; Generalitat de Catalunya [2021SGR00671]; and Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC) [CSIC-PIE201980E100, CSICPIE201980E028, CSIC-PIE202380E095]. FJH has fellowship from the Spanish Ministerio de Ciencia e Innovación [PRE2021-100418]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedOpen ExplorationMinisterio de Ciencia, Innovación y Universidades (España)European CommissionGeneralitat de CatalunyaAgencia Estatal de Investigación (España)Consejo Superior de Investigaciones Científicas (España)Camarasa Rius, María José [0000-0002-4978-6468]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/428978reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-117646RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136307OB-C21info:eu-repo/grantAgreement/AEI/PRE2021-100418/https://doi.org/10.37349/eds.2024.00037Síinfo:eu-repo/semantics/openAccessoai:dnet:digitalcsic_::9f2588d7e279bfdbe9dce781932079612026-05-22T06:33:51Z
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