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

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).