Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1080/14756366.2021.2004591 http://hdl.handle.net/11449/230055 |
Resumo: | We synthesised and screened 18 aromatic derivatives of guanylhydrazones and oximes aromatic for their capacity to bind to dengue virus capsid protein (DENVC). The intended therapeutic target was the hydrophobic cleft of DENVC, which is a region responsible for its anchoring in lipid droplets in the infected cells. The inhibition of this process completely suppresses virus infectivity. Using NMR, we describe five compounds able to bind to the α1-α2 interface in the hydrophobic cleft. Saturation transfer difference experiments showed that the aromatic protons of the ligands are important for the interaction with DENVC. Fluorescence binding isotherms indicated that the selected compounds bind at micromolar affinities, possibly leading to binding-induced conformational changes. NMR-derived docking calculations of ligands showed that they position similarly in the hydrophobic cleft. Cytotoxicity experiments and calculations of in silico drug properties suggest that these compounds may be promising candidates in the search for antivirals targeting DENVC. |
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Repositório Institucional da UNESP |
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Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid proteinDengue virusDENVCdrug-ligand interactionfluorescenceNMRWe synthesised and screened 18 aromatic derivatives of guanylhydrazones and oximes aromatic for their capacity to bind to dengue virus capsid protein (DENVC). The intended therapeutic target was the hydrophobic cleft of DENVC, which is a region responsible for its anchoring in lipid droplets in the infected cells. The inhibition of this process completely suppresses virus infectivity. Using NMR, we describe five compounds able to bind to the α1-α2 interface in the hydrophobic cleft. Saturation transfer difference experiments showed that the aromatic protons of the ligands are important for the interaction with DENVC. Fluorescence binding isotherms indicated that the selected compounds bind at micromolar affinities, possibly leading to binding-induced conformational changes. NMR-derived docking calculations of ligands showed that they position similarly in the hydrophobic cleft. Cytotoxicity experiments and calculations of in silico drug properties suggest that these compounds may be promising candidates in the search for antivirals targeting DENVC.Department of Chemistry Military Institute of Engineering (IME)Institute of Medical Biochemistry Leopoldo de Meis (IBqM) and National Center for Structural Biology and Bioimaging (CENABIO) Federal University of Rio de Janeiro (UFRJ)Multiuser Center for Biomolecular Innovation (CMIB) and Department of Physics Institute of Biosciences Letters and Exact Sciences (IBILCE) São Paulo State University (UNESP)Institute of Medical Biochemistry Leopoldo de Meis (IBqM) Federal University of Rio de Janeiro (UFRJ)Department of Natural Sciences Institute of Biosciences Federal University of the State of Rio de Janeiro (UNIRIO)Multiuser Center for Biomolecular Innovation (CMIB) and Department of Physics Institute of Biosciences Letters and Exact Sciences (IBILCE) São Paulo State University (UNESP)Military Institute of Engineering (IME)Universidade Federal do Rio de Janeiro (UFRJ)Universidade Estadual Paulista (UNESP)Federal University of the State of Rio de Janeiro (UNIRIO)Ortlieb, Liliane O.Caruso, Ícaro P. [UNESP]Mebus-Antunes, Nathane C.Da Poian, Andrea T.Petronilho, Elaine da C.Figueroa-Villar, José DanielNascimento, Claudia J.Almeida, Fabio C. L.2022-04-29T08:37:21Z2022-04-29T08:37:21Z2022-01-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article287-298http://dx.doi.org/10.1080/14756366.2021.2004591Journal of Enzyme Inhibition and Medicinal Chemistry, v. 37, n. 1, p. 287-298, 2022.1475-63741475-6366http://hdl.handle.net/11449/23005510.1080/14756366.2021.20045912-s2.0-85121137057Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal of Enzyme Inhibition and Medicinal Chemistryinfo:eu-repo/semantics/openAccess2022-04-29T08:37:22Zoai:repositorio.unesp.br:11449/230055Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T18:42:47.501321Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein |
title |
Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein |
spellingShingle |
Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein Ortlieb, Liliane O. Dengue virus DENVC drug-ligand interaction fluorescence NMR |
title_short |
Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein |
title_full |
Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein |
title_fullStr |
Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein |
title_full_unstemmed |
Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein |
title_sort |
Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein |
author |
Ortlieb, Liliane O. |
author_facet |
Ortlieb, Liliane O. Caruso, Ícaro P. [UNESP] Mebus-Antunes, Nathane C. Da Poian, Andrea T. Petronilho, Elaine da C. Figueroa-Villar, José Daniel Nascimento, Claudia J. Almeida, Fabio C. L. |
author_role |
author |
author2 |
Caruso, Ícaro P. [UNESP] Mebus-Antunes, Nathane C. Da Poian, Andrea T. Petronilho, Elaine da C. Figueroa-Villar, José Daniel Nascimento, Claudia J. Almeida, Fabio C. L. |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Military Institute of Engineering (IME) Universidade Federal do Rio de Janeiro (UFRJ) Universidade Estadual Paulista (UNESP) Federal University of the State of Rio de Janeiro (UNIRIO) |
dc.contributor.author.fl_str_mv |
Ortlieb, Liliane O. Caruso, Ícaro P. [UNESP] Mebus-Antunes, Nathane C. Da Poian, Andrea T. Petronilho, Elaine da C. Figueroa-Villar, José Daniel Nascimento, Claudia J. Almeida, Fabio C. L. |
dc.subject.por.fl_str_mv |
Dengue virus DENVC drug-ligand interaction fluorescence NMR |
topic |
Dengue virus DENVC drug-ligand interaction fluorescence NMR |
description |
We synthesised and screened 18 aromatic derivatives of guanylhydrazones and oximes aromatic for their capacity to bind to dengue virus capsid protein (DENVC). The intended therapeutic target was the hydrophobic cleft of DENVC, which is a region responsible for its anchoring in lipid droplets in the infected cells. The inhibition of this process completely suppresses virus infectivity. Using NMR, we describe five compounds able to bind to the α1-α2 interface in the hydrophobic cleft. Saturation transfer difference experiments showed that the aromatic protons of the ligands are important for the interaction with DENVC. Fluorescence binding isotherms indicated that the selected compounds bind at micromolar affinities, possibly leading to binding-induced conformational changes. NMR-derived docking calculations of ligands showed that they position similarly in the hydrophobic cleft. Cytotoxicity experiments and calculations of in silico drug properties suggest that these compounds may be promising candidates in the search for antivirals targeting DENVC. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-04-29T08:37:21Z 2022-04-29T08:37:21Z 2022-01-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1080/14756366.2021.2004591 Journal of Enzyme Inhibition and Medicinal Chemistry, v. 37, n. 1, p. 287-298, 2022. 1475-6374 1475-6366 http://hdl.handle.net/11449/230055 10.1080/14756366.2021.2004591 2-s2.0-85121137057 |
url |
http://dx.doi.org/10.1080/14756366.2021.2004591 http://hdl.handle.net/11449/230055 |
identifier_str_mv |
Journal of Enzyme Inhibition and Medicinal Chemistry, v. 37, n. 1, p. 287-298, 2022. 1475-6374 1475-6366 10.1080/14756366.2021.2004591 2-s2.0-85121137057 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Journal of Enzyme Inhibition and Medicinal Chemistry |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
287-298 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808128969240739840 |