2. Academic Validation
  3. Novel indolylarylsulfone derivatives as covalent HIV-1 reverse transcriptase inhibitors specifically targeting the drug-resistant mutant Y181C

Novel indolylarylsulfone derivatives as covalent HIV-1 reverse transcriptase inhibitors specifically targeting the drug-resistant mutant Y181C

  • Bioorg Med Chem. 2021 Jan 15:30:115927. doi: 10.1016/j.bmc.2020.115927.
Ping Gao 1,  Shu Song 1,  Estrella Frutos-Beltrán 2,  Wenxin Li 1,  Bin Sun 3,  Dongwei Kang 1,  Jinmi Zou 1,  Jian Zhang 1,  Christophe Pannecouque 4,  Erik De Clercq 4,  Luis Menéndez-Arias 5,  Peng Zhan 6,  Xinyong Liu 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, PR China.
  • 2 Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), Madrid, Spain.
  • 3 Institute of BioPharmaceutical Research, Liaocheng University, 1 Hunan Road, Liaocheng 252000, PR China.
  • 4 Rega Institute for Medical Research, K. U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
  • 5 Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), Madrid, Spain. Electronic address: lmenendez@cbm.csic.es.
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 7 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 33352387 DOI: 10.1016/j.bmc.2020.115927
Abstract

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.

Keywords

Covalent inhibitor; HIV-1; Indolylarylsulfones; NNRTIs; Y181C.

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