Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine
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 electrophil...
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MDPI AG
2021-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/5/1349 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Shrika G. Harjivan |
| collection | DOAJ |
| description | 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 <i>C</i>-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. |
| first_indexed | 2024-03-09T05:43:31Z |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T05:43:31Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-c6a486e20d8242e2bc641309a64e74da2023-12-03T12:23:25ZengMDPI AGMolecules1420-30492021-03-01265134910.3390/molecules26051349Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug NevirapineShrika G. Harjivan0Catarina Charneira1Inês L. Martins2Sofia A. Pereira3Guadalupe Espadas4Eduard Sabidó5Frederick A. Beland6M. Matilde Marques7Alexandra M. M. Antunes8Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisbon, PortugalCentro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisbon, PortugalCentro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisbon, PortugalCentro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisbon, PortugalProteomics Unit, Centre for Genomic Regulation (CRG), Dr. Aiguader 88, 08003 Barcelona, SpainProteomics Unit, Centre for Genomic Regulation (CRG), Dr. Aiguader 88, 08003 Barcelona, SpainDivision of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USACentro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisbon, PortugalCentro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisbon, PortugalNevirapine (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 <i>C</i>-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.https://www.mdpi.com/1420-3049/26/5/1349covalent histone modificationmass spectrometrydrug-induced adverse reactionscovalent protein adductsnevirapine |
| spellingShingle | 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 Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine Molecules covalent histone modification mass spectrometry drug-induced adverse reactions covalent protein adducts nevirapine |
| title | Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine |
| title_full | Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine |
| title_fullStr | Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine |
| title_full_unstemmed | Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine |
| title_short | Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine |
| title_sort | covalent histone modification by an electrophilic derivative of the anti hiv drug nevirapine |
| topic | covalent histone modification mass spectrometry drug-induced adverse reactions covalent protein adducts nevirapine |
| url | https://www.mdpi.com/1420-3049/26/5/1349 |
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