Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Int J Mol Sci. 2022 Dec 15;23(24):15999. doi: 10.3390/ijms232415999.
As part of our effort to discover drugs that target HIV-1 entry, we report the antiviral activity and crystal structures of two novel inhibitors in a complex with a gp120 core. NBD-14204 showed similar antiviral activity against all the clinical isolates tested. The IC values were in the range of 0.24-0.9 µM with an overall mean of 0.47 ± 0.03 µM, showing slightly better activity against the clinical isolates than against the lab-adapted HIV-1 (IC = 0.96 ± 0.1 µM) Moreover, the antiviral activity of NBD-14208 was less consistent, showing a wider range of IC values (0.66-5.7 µM) with an overall mean of 3 ± 0.25 µM and better activity against subtypes B and D (Mean IC 2.2-2.5 µM) than the A, C and Rec viruses (Mean IC 2.9-3.9 µM). SI of NBD-14204 was about 10-fold higher than NBD-14208, making it a better lead compound for further optimization. In addition, we tested these compounds against S375Y and S375H mutants of gp120, which occurred in some clades and observed these to be sensitive to NBD-14204 and NBD-14208. These inhibitors also showed modest activity against HIV-1 reverse transcriptase. Furthermore, we determined the crystal structures of both inhibitors in complexes with gp120 cores. As expected, both NBD-14204 and NBD-14208 bind primarily within the Phe43 cavity. It is noteworthy that the electron density of the thiazole ring in both structures was poorly defined due to the flexibility of this scaffold, suggesting that these compounds maintain substantial entropy, even when bound to the Phe43 cavity.
作为我们发现靶向 HIV-1 进入的药物的努力的一部分，我们报告了两种新型抑制剂与 gp120 核心复合物的抗病毒活性和晶体结构。NBD-14204 对所有测试的临床分离株均显示出相似的抗病毒活性。IC 值在 0.24-0.9 µM 范围内，平均为 0.47 ± 0.03 µM，对临床分离株的活性略优于对实验室适应的 HIV-1（IC = 0.96 ± 0.1 µM）。此外，NBD-14208 的抗病毒活性不太一致，IC 值范围较宽（0.66-5.7 µM），平均为 3 ± 0.25 µM，对 B 和 D 亚型（平均 IC 2.2-2.5 µM）的活性优于 A、C 和 Re 病毒（平均 IC 2.9-3.9 µM）。NBD-14204 的 SI 约比 NBD-14208 高 10 倍，使其成为进一步优化的更好的先导化合物。此外，我们还测试了这些化合物对 gp120 中的 S375Y 和 S375H 突变体的活性，这些突变体发生在一些分支中，并观察到它们对 NBD-14204 和 NBD-14208 敏感。这些抑制剂对 HIV-1 逆转录酶也表现出适度的活性。此外，我们还确定了两种抑制剂与 gp120 核心复合物的晶体结构。正如预期的那样，NBD-14204 和 NBD-14208 主要结合在 Phe43 腔中。值得注意的是，由于该支架的灵活性，两种结构中噻唑环的电子密度定义不佳，这表明这些化合物即使结合到 Phe43 腔中，也保持着大量的熵。
