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HIV-1 gp120 Antagonists Also Inhibit HIV-1 Reverse Transcriptase by Bridging the NNRTI and NRTI Sites.

Natalie LosadaFrancesc X RuizFrancesca CurreliKevin GruberAlyssa PilchKalyan DasAsim K DebnathEddy Arnold
Published in: Journal of medicinal chemistry (2021)
HIV-1 infection is typically treated using ≥2 drugs, including at least one HIV-1 reverse transcriptase (RT) inhibitor. Drugs targeting RT comprise nucleos(t)ide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). NRTI-triphosphates bind at the polymerase active site and, following incorporation, inhibit DNA elongation. NNRTIs bind at an allosteric pocket ∼10 Å away from the polymerase active site. This study focuses on compounds ("NBD derivatives") originally developed to bind to HIV-1 gp120, some of which inhibit RT. We have determined crystal structures of three NBD compounds in complex with HIV-1 RT, correlating with RT enzyme inhibition and antiviral activity, to develop structure-activity relationships. Intriguingly, these compounds bridge the dNTP and NNRTI-binding sites and inhibit the polymerase activity of RT in the enzymatic assays (IC50 < 5 μM). Two of the lead compounds, NBD-14189 and NBD-14270, show potent antiviral activity (EC50 < 200 nM), and NBD-14270 shows low cytotoxicity (CC50 > 100 μM).
Keyphrases
  • antiretroviral therapy
  • hiv positive
  • hiv infected
  • hiv testing
  • human immunodeficiency virus
  • hiv aids
  • hepatitis c virus
  • men who have sex with men
  • photodynamic therapy
  • small molecule
  • hydrogen peroxide