2. Academic Validation
  3. Discovery, optimization, and target identification of novel coumarin derivatives as HIV-1 reverse transcriptase-associated ribonuclease H inhibitors

Discovery, optimization, and target identification of novel coumarin derivatives as HIV-1 reverse transcriptase-associated ribonuclease H inhibitors

  • Eur J Med Chem. 2021 Dec 5;225:113769. doi: 10.1016/j.ejmech.2021.113769.
Dongwei Kang 1,  Çagil Urhan 2,  Fenju Wei 3,  Estrella Frutos-Beltrán 2,  Lin Sun 3,  Mar Álvarez 2,  Da Feng 3,  Yucen Tao 3,  Christophe Pannecouque 4,  Erik De Clercq 4,  Luis Menéndez-Arias 5,  Xinyong Liu 6,  Peng Zhan 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, 250012, China. Electronic address: [email protected].
  • 2 Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), Madrid, Spain.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, 250012, 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: [email protected].
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, 250012, China. Electronic address: [email protected].
  • 7 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, 250012, China. Electronic address: [email protected].
PMID: 34403976 DOI: 10.1016/j.ejmech.2021.113769
Abstract

Despite significant advances in antiretroviral therapy, acquired immunodeficiency syndrome remains as one of the leading causes of death worldwide. New antiretroviral drugs combined with updated treatment strategies are needed to improve convenience, tolerability, safety, and Antiviral efficacy of available therapies. In this work, a focused library of coumarin derivatives was exploited by cell phenotypic screening to discover novel inhibitors of HIV-1 replication. Five compounds (DW-3, DW-4, DW-11, DW-25 and DW-31) showed moderate activity against wild-type and drug-resistant strains of HIV-1 (IIIB and RES056). Four of those molecules were identified as inhibitors of the viral RT-associated RNase H. Structural modification of the most potent DW-3 and DW-4 led to the discovery of compound 8a. This molecule showed increased potency against wild-type HIV-1 strain (EC50 = 3.94 ± 0.22 μM) and retained activity against a panel of mutant strains, showing EC50 values ranging from 5.62 μM to 202 μM. In enzymatic assays, 8a was found to inhibit the viral RNase H with an IC50 of 12.3 μM. Molecular docking studies revealed that 8a could adopt a binding mode similar to that previously reported for other active site HIV-1 RNase H inhibitors.

Keywords

Coumarin; Drug design; HIV-1; Phenotypic screen; RNase H inhibitor.

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