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Small-Molecule Inhibitor of Flaviviral NS3-NS5 Interaction with Broad-Spectrum Activity and Efficacy In Vivo

Every year, dengue virus (DENV) causes one hundred million infections worldwide that can result in dengue disease and severe dengue. Two other mosquito-borne flaviviruses, i.e., Zika virus (ZIKV) and West Nile virus (WNV), are responsible of prolonged outbreaks and are associated with severe neurolo...

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Autores principales: Celegato, Marta, Sturlese, Mattia, Vasconcelos Costa, Vivian, Trevisan, Marta, Lallo Dias, Angélica Samer, Souza Passos, Ingredy Beatriz, Queiroz-Junior, Celso Martins, Messa, Lorenzo, Favaro, Annagiulia, Moro, Stefano, Teixeira, Mauro Martins, Loregian, Arianna, Mercorelli, Beatrice
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973282/
https://www.ncbi.nlm.nih.gov/pubmed/36622141
http://dx.doi.org/10.1128/mbio.03097-22
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author Celegato, Marta
Sturlese, Mattia
Vasconcelos Costa, Vivian
Trevisan, Marta
Lallo Dias, Angélica Samer
Souza Passos, Ingredy Beatriz
Queiroz-Junior, Celso Martins
Messa, Lorenzo
Favaro, Annagiulia
Moro, Stefano
Teixeira, Mauro Martins
Loregian, Arianna
Mercorelli, Beatrice
author_facet Celegato, Marta
Sturlese, Mattia
Vasconcelos Costa, Vivian
Trevisan, Marta
Lallo Dias, Angélica Samer
Souza Passos, Ingredy Beatriz
Queiroz-Junior, Celso Martins
Messa, Lorenzo
Favaro, Annagiulia
Moro, Stefano
Teixeira, Mauro Martins
Loregian, Arianna
Mercorelli, Beatrice
author_sort Celegato, Marta
collection PubMed
description Every year, dengue virus (DENV) causes one hundred million infections worldwide that can result in dengue disease and severe dengue. Two other mosquito-borne flaviviruses, i.e., Zika virus (ZIKV) and West Nile virus (WNV), are responsible of prolonged outbreaks and are associated with severe neurological diseases, congenital defects, and eventually death. These three viruses, despite their importance for global public health, still lack specific drug treatments. Here, we describe the structure-guided discovery of small molecules with pan-flavivirus antiviral potential by a virtual screening of ~1 million structures targeting the NS3-NS5 interaction surface of different flaviviruses. Two molecules inhibited the interaction between DENV NS3 and NS5 in vitro and the replication of all DENV serotypes as well as ZIKV and WNV and exhibited low propensity to select resistant viruses. Remarkably, one molecule demonstrated efficacy in a mouse model of dengue by reducing peak viremia, viral load in target organs, and associated tissue pathology. This study provides the proof of concept that targeting the flaviviral NS3-NS5 interaction is an effective therapeutic strategy able to reduce virus replication in vivo and discloses new chemical scaffolds that could be further developed, thus providing a significant milestone in the development of much awaited broad-spectrum antiflaviviral drugs.
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spelling pubmed-99732822023-03-01 Small-Molecule Inhibitor of Flaviviral NS3-NS5 Interaction with Broad-Spectrum Activity and Efficacy In Vivo Celegato, Marta Sturlese, Mattia Vasconcelos Costa, Vivian Trevisan, Marta Lallo Dias, Angélica Samer Souza Passos, Ingredy Beatriz Queiroz-Junior, Celso Martins Messa, Lorenzo Favaro, Annagiulia Moro, Stefano Teixeira, Mauro Martins Loregian, Arianna Mercorelli, Beatrice mBio Research Article Every year, dengue virus (DENV) causes one hundred million infections worldwide that can result in dengue disease and severe dengue. Two other mosquito-borne flaviviruses, i.e., Zika virus (ZIKV) and West Nile virus (WNV), are responsible of prolonged outbreaks and are associated with severe neurological diseases, congenital defects, and eventually death. These three viruses, despite their importance for global public health, still lack specific drug treatments. Here, we describe the structure-guided discovery of small molecules with pan-flavivirus antiviral potential by a virtual screening of ~1 million structures targeting the NS3-NS5 interaction surface of different flaviviruses. Two molecules inhibited the interaction between DENV NS3 and NS5 in vitro and the replication of all DENV serotypes as well as ZIKV and WNV and exhibited low propensity to select resistant viruses. Remarkably, one molecule demonstrated efficacy in a mouse model of dengue by reducing peak viremia, viral load in target organs, and associated tissue pathology. This study provides the proof of concept that targeting the flaviviral NS3-NS5 interaction is an effective therapeutic strategy able to reduce virus replication in vivo and discloses new chemical scaffolds that could be further developed, thus providing a significant milestone in the development of much awaited broad-spectrum antiflaviviral drugs. American Society for Microbiology 2023-01-09 /pmc/articles/PMC9973282/ /pubmed/36622141 http://dx.doi.org/10.1128/mbio.03097-22 Text en Copyright © 2023 Celegato et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Celegato, Marta
Sturlese, Mattia
Vasconcelos Costa, Vivian
Trevisan, Marta
Lallo Dias, Angélica Samer
Souza Passos, Ingredy Beatriz
Queiroz-Junior, Celso Martins
Messa, Lorenzo
Favaro, Annagiulia
Moro, Stefano
Teixeira, Mauro Martins
Loregian, Arianna
Mercorelli, Beatrice
Small-Molecule Inhibitor of Flaviviral NS3-NS5 Interaction with Broad-Spectrum Activity and Efficacy In Vivo
title Small-Molecule Inhibitor of Flaviviral NS3-NS5 Interaction with Broad-Spectrum Activity and Efficacy In Vivo
title_full Small-Molecule Inhibitor of Flaviviral NS3-NS5 Interaction with Broad-Spectrum Activity and Efficacy In Vivo
title_fullStr Small-Molecule Inhibitor of Flaviviral NS3-NS5 Interaction with Broad-Spectrum Activity and Efficacy In Vivo
title_full_unstemmed Small-Molecule Inhibitor of Flaviviral NS3-NS5 Interaction with Broad-Spectrum Activity and Efficacy In Vivo
title_short Small-Molecule Inhibitor of Flaviviral NS3-NS5 Interaction with Broad-Spectrum Activity and Efficacy In Vivo
title_sort small-molecule inhibitor of flaviviral ns3-ns5 interaction with broad-spectrum activity and efficacy in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973282/
https://www.ncbi.nlm.nih.gov/pubmed/36622141
http://dx.doi.org/10.1128/mbio.03097-22
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