Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China.
Department of Pharmacy, Qilu Hospital of Shandong University, 107 West Culture Road, Jinan 250012, China.
Molecules. 2022 Nov 7;27(21):7640. doi: 10.3390/molecules27217640.
The AIDS pandemic is still of importance. HIV-1 and HIV-2 are the causative agents of this pandemic, and in the absence of a viable vaccine, drugs are continually required to provide quality of life for infected patients. The HIV capsid (CA) protein performs critical functions in the life cycle of HIV-1 and HIV-2, is broadly conserved across major strains and subtypes, and is underexploited. Therefore, it has become a therapeutic target of interest. Here, we report a novel series of 2-pyridone-bearing phenylalanine derivatives as HIV capsid modulators. Compound FTC-2 is the most potent anti-HIV-1 compound in the new series of compounds, with acceptable cytotoxicity in MT-4 cells (selectivity index HIV-1 > 49.57; HIV-2 > 17.08). However, compound TD-1a has the lowest EC50 in the anti-HIV-2 assays (EC50 = 4.86 ± 1.71 μM; CC50= 86.54 ± 29.24 μM). A water solubility test found that TD-1a showed a moderately increased water solubility compared with PF74, while the water solubility of FTC-2 was improved hundreds of times. Furthermore, we use molecular simulation studies to provide insight into the molecular contacts between the new compounds and HIV CA. We also computationally predict drug-like properties and metabolic stability for FTC-2 and TD-1a. Based on this analysis, TD-1a is predicted to have improved drug-like properties and metabolic stability over PF74. This study increases the repertoire of CA modulators and has important implications for developing anti-HIV agents with novel mechanisms, especially those that inhibit the often overlooked HIV-2.
艾滋病大流行仍然很重要。HIV-1 和 HIV-2 是导致这一大流行的病原体，在没有可行疫苗的情况下，需要不断使用药物来提高感染患者的生活质量。HIV 衣壳 (CA) 蛋白在 HIV-1 和 HIV-2 的生命周期中发挥着关键作用，在主要毒株和亚型中广泛保守，但尚未得到充分利用。因此，它已成为一个有吸引力的治疗靶点。在这里，我们报告了一系列新的含 2-吡啶酮的苯丙氨酸衍生物作为 HIV 衣壳调节剂。化合物 FTC-2 是新系列化合物中抗 HIV-1 最有效的化合物，在 MT-4 细胞中具有可接受的细胞毒性（选择性指数 HIV-1 > 49.57；HIV-2 > 17.08）。然而，化合物 TD-1a 在抗 HIV-2 测定中的 EC50 最低（EC50 = 4.86 ± 1.71 μM；CC50 = 86.54 ± 29.24 μM）。水溶性测试发现，TD-1a 的水溶性与 PF74 相比略有提高，而 FTC-2 的水溶性提高了数百倍。此外，我们使用分子模拟研究提供了对新化合物与 HIV CA 之间分子接触的深入了解。我们还计算预测了 FTC-2 和 TD-1a 的类药性和代谢稳定性。基于此分析，TD-1a 被预测在类药性和代谢稳定性方面优于 PF74。这项研究增加了 CA 调节剂的种类，并对开发具有新型机制的抗 HIV 药物具有重要意义，特别是那些抑制经常被忽视的 HIV-2 的药物。
