Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, United States.
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, United States.
J Med Chem. 2021 Nov 25;64(22):16530-16540. doi: 10.1021/acs.jmedchem.1c01104. Epub 2021 Nov 4.
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 < 5 μM). Two of the lead compounds, NBD-14189 and NBD-14270, show potent antiviral activity (EC < 200 nM), and NBD-14270 shows low cytotoxicity (CC > 100 μM).
HIV-1 感染通常采用至少两种药物进行治疗，包括至少一种 HIV-1 逆转录酶（RT）抑制剂。针对 RT 的药物包括核苷（酸）RT 抑制剂（NRTIs）和非核苷 RT 抑制剂（NNRTIs）。NRTI-三磷酸与聚合酶活性位点结合，在掺入后抑制 DNA 延伸。NNRTIs 结合在距聚合酶活性位点约 10 Å 的变构口袋中。本研究关注最初开发用于结合 HIV-1 gp120 的化合物（“NBD 衍生物”），其中一些化合物抑制 RT。我们已经确定了三种 NBD 化合物与 HIV-1 RT 复合物的晶体结构，与 RT 酶抑制和抗病毒活性相关，以开发结构-活性关系。有趣的是，这些化合物桥接 dNTP 和 NNRTI 结合位点，并在酶促测定中抑制 RT 的聚合酶活性（IC < 5 μM）。两种先导化合物，NBD-14189 和 NBD-14270，表现出很强的抗病毒活性（EC < 200 nM），而 NBD-14270 表现出低细胞毒性（CC > 100 μM）。
