Covalent histone modification by an electrophilic derivative of the anti-HIV drug nevirapine
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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 immunodefi-ciency 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 evidenced to be potential hot spots for NVP incorporation. In fact, a remarkable selectivity to the imidazole ring of histidine was observed: 3 out of the 11 histidine residues of histones were NVP-modified. This suggests that NVP-modified histidine residues of histones are prospective markers of this an-ti-HIV drug bioactivation and/or toxicity. Importantly, NVP-derived modifications were iden-tified at sites known to determine chromatin structure (e.g. H4H76) and that can undergo multi-ple types of PTMs (e.g. H2BK47, H4H76). These results open new insights into the molecular mechanisms of drug-induced adverse reactions.
INSTRUMENT(S): LTQ Orbitrap
ORGANISM(S): Homo Sapiens (human)
SUBMITTER: guadalupe espadas
LAB HEAD: Eduard Sabidó
PROVIDER: PXD023751 | Pride | 2021-03-08
REPOSITORIES: Pride
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