Structure-driven discovery of α,γ-diketoacid inhibitors against UL89 herpesvirus terminase

This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Detalhes bibliográficos
Autores: Bongarzone, Salvatore, Nadal, Marta, Kaczmarska, Zuzanna, Machón, Cristina, Álvarez, Mercedes, Albericio, Fernando, Coll, Miquel
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/174769
Acesso em linha:http://hdl.handle.net/10261/174769
Access Level:acceso abierto
Palavra-chave:Crystal structures
Drug discovery and Drug delivery systems
Molecular structure
Structure-activity relationship
Viruses
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spelling Structure-driven discovery of α,γ-diketoacid inhibitors against UL89 herpesvirus terminaseBongarzone, SalvatoreNadal, MartaKaczmarska, ZuzannaMachón, CristinaÁlvarez, MercedesAlbericio, FernandoColl, MiquelCrystal structuresDrug discovery and Drug delivery systemsMolecular structureStructure-activity relationshipVirusesThis is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.Human cytomegalovirus (HCMV) is an opportunistic pathogen causing a variety of severe viral infections, including irreversible congenital disabilities. Nowadays, HCMV infection is treated by inhibiting the viral DNA polymerase. However, DNA polymerase inhibitors have several drawbacks. An alternative strategy is to use compounds against the packaging machinery or terminase complex, which is essential for viral replication. Our discovery that raltegravir (1), a human immunodeficiency virus drug, inhibits the nuclease function of UL89, one of the protein subunits of the complex, prompted us to further develop terminase inhibitors. On the basis of the structure of 1, a library of diketoacid (α,γ-DKA and β,δ-DKA) derivatives were synthesized and tested for UL89-C nuclease activity. The mode of action of α,γ-DKA derivatives on the UL89 active site was elucidated by using X-ray crystallography, molecular docking, and in vitro experiments. Our studies identified α,γ-DKA derivative 14 able to inhibit UL89 in vitro in the low micromolar range, making 14 an optimal candidate for further development and virus-infected cell assay.S.B. was supported by COFUND/Marie Curie fellowship (European Commission FP7). CM was supported by the RYC fellowship (grant RYC2011-09071) from the Ministerio de Economia y Competividad (MINECO). The Institute for Research in Biomedicine Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO. The work was partially supported by grants from the MINECO (grants BFU2011-22588, CTQ2012-30930, CTQ2015-67870P, BFU2014-53550-P, BFU2017-83720-P, Marí a de Maeztu Award of Excellence MDM-2014-0435), the Generalitat de Catalunya (grants 2014 SGR 1530 and 2014 SGR 137) and the European Commission FP7 (Project SILVER-GA no. 260644).Peer reviewedAmerican Chemical SocietyAgencia Estatal de Investigación (España)European CommissionMinisterio de Economía y Competitividad (España)Institute for Research in Biomedicine (Spain)Generalitat de CatalunyaBongarzone, Salvatore [0000-0002-1309-3045]Álvarez, Mercedes [0000-0002-2025-9111]Coll, Miquel [0000-0003-4471-8674]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/174769reponame: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##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#BFU2017-83720-P/AEI/10.13039/501100011033info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2015-67870-Pinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2014-53550-Pinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/BFU2017-83720-Pinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/MDM-2014-0435info:eu-repo/grantAgreement/EC/FP7/260644http://dx.doi.org/10.1021/acsomega.8b01472Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1747692026-05-22T06:33:51Z
dc.title.none.fl_str_mv Structure-driven discovery of α,γ-diketoacid inhibitors against UL89 herpesvirus terminase
title Structure-driven discovery of α,γ-diketoacid inhibitors against UL89 herpesvirus terminase
spellingShingle Structure-driven discovery of α,γ-diketoacid inhibitors against UL89 herpesvirus terminase
Bongarzone, Salvatore
Crystal structures
Drug discovery and Drug delivery systems
Molecular structure
Structure-activity relationship
Viruses
title_short Structure-driven discovery of α,γ-diketoacid inhibitors against UL89 herpesvirus terminase
title_full Structure-driven discovery of α,γ-diketoacid inhibitors against UL89 herpesvirus terminase
title_fullStr Structure-driven discovery of α,γ-diketoacid inhibitors against UL89 herpesvirus terminase
title_full_unstemmed Structure-driven discovery of α,γ-diketoacid inhibitors against UL89 herpesvirus terminase
title_sort Structure-driven discovery of α,γ-diketoacid inhibitors against UL89 herpesvirus terminase
dc.creator.none.fl_str_mv Bongarzone, Salvatore
Nadal, Marta
Kaczmarska, Zuzanna
Machón, Cristina
Álvarez, Mercedes
Albericio, Fernando
Coll, Miquel
author Bongarzone, Salvatore
author_facet Bongarzone, Salvatore
Nadal, Marta
Kaczmarska, Zuzanna
Machón, Cristina
Álvarez, Mercedes
Albericio, Fernando
Coll, Miquel
author_role author
author2 Nadal, Marta
Kaczmarska, Zuzanna
Machón, Cristina
Álvarez, Mercedes
Albericio, Fernando
Coll, Miquel
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Agencia Estatal de Investigación (España)
European Commission
Ministerio de Economía y Competitividad (España)
Institute for Research in Biomedicine (Spain)
Generalitat de Catalunya
Bongarzone, Salvatore [0000-0002-1309-3045]
Álvarez, Mercedes [0000-0002-2025-9111]
Coll, Miquel [0000-0003-4471-8674]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Crystal structures
Drug discovery and Drug delivery systems
Molecular structure
Structure-activity relationship
Viruses
topic Crystal structures
Drug discovery and Drug delivery systems
Molecular structure
Structure-activity relationship
Viruses
description This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
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/10261/174769
url http://hdl.handle.net/10261/174769
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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#PLACEHOLDER_PARENT_METADATA_VALUE#
BFU2017-83720-P/AEI/10.13039/501100011033
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2015-67870-P
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2014-53550-P
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/BFU2017-83720-P
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/MDM-2014-0435
info:eu-repo/grantAgreement/EC/FP7/260644
http://dx.doi.org/10.1021/acsomega.8b01472
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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