Harjivan, Shrika G.Charneira, CatarinaMartins, Inês L.Pereira, Sofia A.Espadas, GuadalupeSabidó Aguadé, Eduard, 1981-Beland, Frederick A.Marques, M. MatildeAntunes, Alexandra M. M.2021-05-252021-05-252021Harjivan 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/molecules260513491420-3049http://hdl.handle.net/10230/47649Nevirapine (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.application/pdfeng© 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/)VIH (Virus) -- TractamentMedicaments -- Efectes secundarisinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.3390/molecules26051349info:eu-repo/semantics/openAccess