Novel indolylarylsulfone derivatives as covalent HIV-1 reverse transcriptase inhibitors specifically targeting the drug-resistant mutant Y181C
| Autor: | Jian Zhang, Wenxin Li, Peng Zhan, Dongwei Kang, Ping Gao, Jinmi Zou, Shu Song, Estrella Frutos-Beltrán, Luis Menéndez-Arias, Erik De Clercq, Christophe Pannecouque, Bin Sun, Xinyong Liu |
|---|---|
| Přispěvatelé: | Ministerio de Ciencia e Innovación (España), Fundación Ramón Areces |
| Rok vydání: | 2020 |
| Předmět: |
Nevirapine
Indoles Anti-HIV Agents Clinical Biochemistry Mutant Pharmaceutical Science Etravirine Drug resistance medicine.disease_cause 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Drug Resistance Viral Indolylarylsulfones medicine Nucleotide Sulfones Covalent inhibitor Molecular Biology chemistry.chemical_classification Mutation Y181C Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry virus diseases Reverse transcriptase HIV Reverse Transcriptase 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Rilpivirine NNRTIs HIV-1 Molecular Medicine Reverse Transcriptase Inhibitors medicine.drug |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1464-3391 |
| Popis: | Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. However, emergent and transmitted drug resistance compromise their efficacy in the clinical setting. Y181C is selected in patients receiving nevirapine, etravirine and rilpivirine, and together with K103N is the most prevalent NNRTI-associated mutation in HIV-infected patients. Herein, we report on the design, synthesis and biological evaluation of a novel series of indolylarylsulfones bearing acrylamide or ethylene sulfonamide reactive groups as warheads to inactivate Cys181-containing HIV-1 RT via a Michael addition reaction. Compounds I-7 and I-9 demonstrated higher selectivity towards the Y181C mutant than against the wild-type RT, in nucleotide incorporation inhibition assays. The larger size of the NNRTI binding pocket in the mutant enzyme facilitates a better fit for the active compounds, while stacking interactions with Phe227 and Pro236 contribute to inhibitor binding. Mass spectrometry data were consistent with the covalent modification of the RT, although off-target reactivity constitutes a major limitation for further development of the described inhibitors. by grants PID2019-104176RB-I00/AEI/10.13039/501100011033) (Spanish Ministry of Science and Innovation) and 2019AEP001 (CSIC), as well as an institutional grant of Fundación Ramón Areces (awarded to the CBMSO). |
| Databáze: | OpenAIRE |
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