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).

中文翻译：

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HIV-1 gp120 拮抗剂还通过桥接 NNRTI 和 NRTI 位点抑制 HIV-1 逆转录酶

HIV-1 感染通常使用 ≥2 种药物治疗，包括至少一种 HIV-1 逆转录酶 (RT) 抑制剂。靶向RT的药物包括核苷（酸）RT抑制剂（NRTI）和非核苷RT抑制剂（NNRTI）。NRTI-三磷酸结合在聚合酶活性位点，并在掺入后抑制 DNA 延伸。NNRTI 结合在距聚合酶活性位点约 10 Å 的变构袋上。本研究重点关注最初开发用于与 HIV-1 gp120 结合的化合物（“NBD 衍生物”），其中一些化合物会抑制 RT。我们确定了与 HIV-1 RT 复合的三种 NBD 化合物的晶体结构，与 RT 酶抑制和抗病毒活性相关，以建立结构-活性关系。有趣的是，这些化合物桥接 dNTP 和 NNRTI 结合位点，并在酶测定中抑制 RT 的聚合酶活性 (IC ₅₀ < 5 μM)。其中两种先导化合物 NBD-14189 和 NBD-14270 显示出有效的抗病毒活性 (EC ₅₀ < 200 nM)，而 NBD-14270 显示出较低的细胞毒性 (CC ₅₀ > 100 μM)。