Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine

Shrika G. Harjivan, Catarina Charneira, Inês L. Martins, Sofia A. Pereira, Guadalupe Espadas, Eduard Sabidó, Frederick A. Beland, M. Matilde Marques, Alexandra M.M. Antunes

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4 Citations (Scopus)
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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.

Original languageEnglish
Article number1349
Issue number5
Publication statusPublished - 3 Mar 2021


  • covalent histone modification
  • covalent protein adducts
  • drug-induced adverse reactions
  • mass spectrometry
  • nevirapine


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