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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| Language: | English |
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Open Exploration
2024-02-01
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| Series: | Exploration of Drug Science |
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| Online Access: | https://www.explorationpub.com/uploads/Article/A100837/100837.pdf |
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| author | Francisco Javier Hermoso-Pinilla Aitor Valdivia María-José Camarasa Tiziana Ginex Francisco Javier Luque |
| author_facet | Francisco Javier Hermoso-Pinilla Aitor Valdivia María-José Camarasa Tiziana Ginex Francisco Javier Luque |
| author_sort | Francisco Javier Hermoso-Pinilla |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-f2fc3ed62908438e8790fa85a4adfeb2 |
| institution | Kabale University |
| issn | 2836-7677 |
| language | English |
| publishDate | 2024-02-01 |
| publisher | Open Exploration |
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| series | Exploration of Drug Science |
| spelling | doaj-art-f2fc3ed62908438e8790fa85a4adfeb22025-02-08T03:44:56ZengOpen ExplorationExploration of Drug Science2836-76772024-02-01218511610.37349/eds.2024.00037Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discoveryFrancisco Javier Hermoso-Pinilla0https://orcid.org/0000-0002-8476-2728Aitor Valdivia1https://orcid.org/0000-0003-4862-0850María-José Camarasa2https://orcid.org/0000-0002-4978-6468Tiziana Ginex3https://orcid.org/0000-0002-5739-8713Francisco Javier Luque4https://orcid.org/0000-0002-8049-3567Departament de Nutrició, Ciències de l’Alimentació i Gastronomia, Facultat de Farmàcia i Ciències de l’Alimentació, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08021 Santa Coloma de Gramenet, SpainDepartament de Nutrició, Ciències de l’Alimentació i Gastronomia, Facultat de Farmàcia i Ciències de l’Alimentació, Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, 08021 Santa Coloma de Gramenet, SpainInstituto de Química Médica (IQM, CSIC), 28006 Madrid, SpainPharmacelera, Parc Científic de Barcelona (PCB), 08028 Barcelona, SpainDepartament de Nutrició, Ciències de l’Alimentació i Gastronomia, Facultat de Farmàcia i Ciències de l’Alimentació, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08021 Santa Coloma de Gramenet, Spain; Departament de Nutrició, Ciències de l’Alimentació i Gastronomia, Facultat de Farmàcia i Ciències de l’Alimentació, Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, 08021 Santa Coloma de Gramenet, SpainThe 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.https://www.explorationpub.com/uploads/Article/A100837/100837.pdfinfluenza a virushemagglutininfusion inhibitorsdrug designtargeted protein degradationantiviral proteolysis targeting chimeras |
| spellingShingle | Francisco Javier Hermoso-Pinilla Aitor Valdivia María-José Camarasa Tiziana Ginex Francisco Javier Luque Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery Exploration of Drug Science influenza a virus hemagglutinin fusion inhibitors drug design targeted protein degradation antiviral proteolysis targeting chimeras |
| title | 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_short | 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 |
| topic | influenza a virus hemagglutinin fusion inhibitors drug design targeted protein degradation antiviral proteolysis targeting chimeras |
| url | https://www.explorationpub.com/uploads/Article/A100837/100837.pdf |
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