Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Ji'nan, Shandong 250012, People's Republic of China.
Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States.
J Med Chem. 2020 May 14;63(9):4790-4810. doi: 10.1021/acs.jmedchem.0c00015. Epub 2020 Apr 29.
The HIV-1 CA protein has gained remarkable attention as a promising therapeutic target for the development of new antivirals, due to its pivotal roles in HIV-1 replication (structural and regulatory). Herein, we report the design and synthesis of three series of benzenesulfonamide-containing phenylalanine derivatives obtained by further structural modifications of to aid in the discovery of more potent and drug-like HIV-1 CA inhibitors. Structure-activity relationship studies of these compounds led to the identification of new phenylalanine derivatives with a piperazinone moiety, represented by compound , which exhibited anti-HIV-1 activity 5.78-fold better than . Interestingly, also showed anti-HIV-2 activity (EC = 31 nM), with almost 120 times increased potency over . However, due to the higher significance of HIV-1 as compared to HIV-2 for the human population, this manuscript focuses on the mechanism of action of our compounds in the context of HIV-1. SPR studies on representative compounds confirmed CA as the binding target. The action stage determination assay demonstrated that these inhibitors exhibited antiviral activities with a dual-stage inhibition profile. The early-stage inhibitory activity of compound was 6.25 times more potent as compared to but appeared to work via the accelerating capsid core assembly rather than stabilization. However, the mechanism by which they exert their antiviral activity in the late stage appears to be the same as with less infectious HIV-1 virions produced in their presence, as judged p24 content studies. MD simulations provided the key rationale for the promising antiviral potency of . Additionally, exhibited a modest increase in HLM and human plasma metabolic stabilities as compared to , as well as a moderately improved pharmacokinetic profile, favorable oral bioavailability, and no acute toxicity. These studies provide insights and serve as a starting point for subsequent medicinal chemistry efforts in optimizing these promising HIV inhibitors.
HIV-1 CA 蛋白作为开发新型抗病毒药物的有前途的治疗靶标引起了人们的极大关注，因为它在 HIV-1 复制（结构和调节）中起着关键作用。在此，我们报告了通过进一步结构修饰设计和合成的包含苯磺酰胺的苯丙氨酸衍生物系列，以帮助发现更有效和类药性的 HIV-1 CA 抑制剂。对这些化合物的构效关系研究导致发现了具有哌嗪酮部分的新苯丙氨酸衍生物，以化合物 为代表，其抗 HIV-1 活性比 好 5.78 倍。有趣的是， 还显示出抗 HIV-2 活性（EC = 31 nM），与 相比，效力增加了近 120 倍。然而，由于 HIV-1 对人类的重要性高于 HIV-2，因此本文重点介绍了我们的化合物在 HIV-1 背景下的作用机制。代表性化合物的 SPR 研究证实 CA 是结合靶标。作用阶段确定测定表明，这些抑制剂表现出具有双重抑制谱的抗病毒活性。与 相比，化合物 的早期抑制活性强 6.25 倍，但似乎通过加速衣壳核心组装而不是稳定起作用。然而，它们在晚期发挥抗病毒活性的机制似乎与 相同，因为在它们存在的情况下产生的感染性 HIV-1 病毒粒子较少，如 p24 含量研究判断的那样。MD 模拟为 具有有希望的抗病毒效力提供了关键依据。此外，与 相比， 在人肝微粒体和人血浆中的代谢稳定性略有提高，药代动力学特征也有所改善，口服生物利用度良好，且无急性毒性。这些研究为后续优化这些有前途的 HIV 抑制剂的药物化学研究提供了思路和起点。
