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

• Published in: Journal of medicinal chemistry 2021-11, Vol.64 (22), p.16530-16540
• Main Authors: Losada, Natalie, Ruiz, Francesc X, Curreli, Francesca, Gruber, Kevin, Pilch, Alyssa, Das, Kalyan, Debnath, Asim K, Arnold, Eddy
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Binding Sites; Cell Line; Crystallography, X-Ray; HIV Envelope Protein gp120 - antagonists & inhibitors; HIV Reverse Transcriptase - antagonists & inhibitors; HIV-1 - drug effects; HIV-1 - enzymology; Humans; Molecular Docking Simulation; Molecular Structure; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01104

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).