Open AccessHIV-1 gp120 Antagonists Also Inhibit HIV-1 Reverse Transcriptase by Bridging the NNRTI and NRTI Sites
Author(s) -
Natalie Losada,
Francesc Xavier Ruiz,
Francesca Curreli,
Kevin Gruber,
Alyssa Pilch,
Kalyan Das,
Asim K. Debnath,
Eddy Arnold
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c01104
Subject(s) - chemistry , reverse transcriptase , allosteric regulation , enzyme , polymerase , nucleoside , nucleoside reverse transcriptase inhibitor , dna polymerase , reverse transcriptase inhibitor , stereochemistry , virology , biochemistry , rna , biology , gene
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 (IC 50 < 5 μM). Two of the lead compounds, NBD-14189 and NBD-14270, show potent antiviral activity (EC 50 < 200 nM), and NBD-14270 shows low cytotoxicity (CC 50 > 100 μM).