Covalent histone modification by an electrophilic derivative of the anti-HIV drug nevirapine

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  • dc.contributor.author Harjivan, Shrika G.
  • dc.contributor.author Charneira, Catarina
  • dc.contributor.author Martins, Inês L.
  • dc.contributor.author Pereira, Sofia A.
  • dc.contributor.author Espadas, Guadalupe
  • dc.contributor.author Sabidó Aguadé, Eduard, 1981-
  • dc.contributor.author Beland, Frederick A.
  • dc.contributor.author Marques, M. Matilde
  • dc.contributor.author Antunes, Alexandra M. M.
  • dc.date.accessioned 2021-05-25T12:23:03Z
  • dc.date.available 2021-05-25T12:23:03Z
  • dc.date.issued 2021
  • dc.description.abstract Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor widely used in combined antiretroviral therapy and to prevent mother-to-child transmission of the human immunodeficiency virus type 1, is associated with several adverse side effects. Using 12-mesyloxy-nevirapine, a model electrophile of the reactive metabolites derived from the NVP Phase I metabolite, 12-hydroxy-NVP, we demonstrate that the nucleophilic core and C-terminal residues of histones are targets for covalent adduct formation. We identified multiple NVP-modification sites at lysine (e.g., H2BK47, H4K32), histidine (e.g., H2BH110, H4H76), and serine (e.g., H2BS33) residues of the four histones using a mass spectrometry-based bottom-up proteomic analysis. In particular, H2BK47, H2BH110, H2AH83, and H4H76 were found to be potential hot spots for NVP incorporation. Notably, a remarkable selectivity to the imidazole ring of histidine was observed, with modification by NVP detected in three out of the 11 histidine residues of histones. This suggests that NVP-modified histidine residues of histones are prospective markers of the drug's bioactivation and/or toxicity. Importantly, NVP-derived modifications were identified at sites known to determine chromatin structure (e.g., H4H76) or that can undergo multiple types of post-translational modifications (e.g., H2BK47, H4H76). These results open new insights into the molecular mechanisms of drug-induced adverse reactions.
  • dc.description.sponsorship This work was supported in part by the PRIME-XS project, grant agreement number 262067, funded by the European Union seventh Framework Programme. We also thank Fundação para a Ciência e a Tecnologia (FCT), Portugal, for financial support through projects UID/QUI/00100/2020 (to CQE), RECI/QEQ-MED/0330/2012 and PTDC/QUI-QAN/32242/2017, as well as contract CEECIND/02001/2017 (to A.M.M.A) and doctoral fellowships SFRH/BD/80690/2011 (to SGH), SFRH/BD/75426/2010 (to ILM), and SFRH/BD/102846/2014 (to CC). Joint funding from FCT and the COMPETE Program through grant SAICTPAC/0019/2015 and RNEM-LISBOA-01-0145-FEDER-022125 funding are also gratefully acknowledged. The CRG/UPF Proteomics Unit is part of the “Plataforma de Recursos Biomoleculares y Bioinformáticos (ProteoRed)” supported by grant PT13/0001 of the Instituto de Salud Carlos III (ISCIII)
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Harjivan S, Charneira C, Martins IL, Pereira SA, Espadas G, Sabidó E et al. Covalent histone modification by an electrophilic derivative of the anti-HIV drug nevirapine. Molecules. 2021 Mar 3;26(5):1349. DOI: 10.3390/molecules26051349
  • dc.identifier.doi http://dx.doi.org/10.3390/molecules26051349
  • dc.identifier.issn 1420-3049
  • dc.identifier.uri http://hdl.handle.net/10230/47649
  • dc.language.iso eng
  • dc.publisher MDPI
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/262067
  • dc.rights © 2021 by Shrika G. Hajivan et al. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/4.0/)
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri https://creativecommons.org/licenses/by/4.0/
  • dc.subject.other VIH (Virus) -- Tractament
  • dc.subject.other Medicaments -- Efectes secundaris
  • dc.title Covalent histone modification by an electrophilic derivative of the anti-HIV drug nevirapine
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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