4-苯基-1H-1,2,3-三唑苯丙氨酸衍生物的设计、合成和构效关系作为新型HIV-1衣壳抑制剂，具有良好的抗病毒活性。,European Journal of Medicinal Chemistry

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4-苯基-1H-1,2,3-三唑苯丙氨酸衍生物的设计、合成和构效关系作为新型HIV-1衣壳抑制剂，具有良好的抗病毒活性。
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-24 , DOI: 10.1016/j.ejmech.2020.112085
Lin Sun ₁ , Tianguang Huang ₁ , Alexej Dick ₂ , Megan E Meuser ₂ , Waleed A Zalloum ₃ , Chin-Ho Chen ₄ , Xiao Ding ₁ , Ping Gao ₁ , Simon Cocklin ₂ , Kuo-Hsiung Lee ₅ , Peng Zhan ₁ , Xinyong Liu ₁

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HIV-1 CA 参与病毒复制周期的不同阶段，在早期（脱壳、逆转录、核输入、整合）和晚期事件（组装）中发挥重要作用。最近的努力已证明 HIV-1 CA 蛋白是开发新型抗病毒药物的前瞻性治疗靶点。研究最广泛的 CA 抑制剂是 PF-3450074（PF-74，由辉瑞公司发现），其目标是 CA 六聚体内的原体间口袋。在此，我们报道了一系列基于PF-74支架的4-苯基-1H-1,2,3-三唑苯丙氨酸衍生物作为HIV-1 CA抑制剂的设计、合成和生物学评价。大多数类似物都表现出有效的抗病毒活性，其中6a-9的抗HIV-1活性（EC50 = 3.13 μM）尤为突出。所选化合物（6a-9、6a-10、5b）的 SPR 结合测定表明与重组 CA 蛋白存在直接有效的相互作用。作用机制研究还表明，6a-9 在 HIV-1 复制的早期和晚期均显示出作用。为了探索此处提出的类似物的潜在结合模式，通过 MD 模拟分析 6a-9，以预测其与 HIV-1 CA 单体活性位点的结合。总之，这一系列新型抗病毒药物可以作为开发新一代 HIV-1 治疗方案的起点，并凸显了 CA 作为治疗靶点的潜力。

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Design, synthesis and structure-activity relationships of 4-phenyl-1H-1,2,3-triazole phenylalanine derivatives as novel HIV-1 capsid inhibitors with promising antiviral activities.

HIV-1 CA is involved in different stages of the viral replication cycle, performing essential roles in both early (uncoating, reverse transcription, nuclear import, integration) and late events (assembly). Recent efforts have demonstrated HIV-1 CA protein as a prospective therapeutic target for the development of new antivirals. The most extensively studied CA inhibitor, PF-3450074 (PF-74, discovered by Pfizer), that targets an inter-protomer pocket within the CA hexamer. Herein we reported the design, synthesis, and biological evaluation of a series of 4-phenyl-1H-1,2,3-triazole phenylalanine derivatives as HIV-1 CA inhibitors based on PF-74 scaffold. Most of the analogues demonstrated potent antiviral activities, among them, the anti-HIV-1 activity of 6a-9 (EC50 = 3.13 μM) is particularly prominent. The SPR binding assay of selected compounds (6a-9, 6a-10, 5b) suggested direct and effective interaction with recombinant CA proteins. The mechanism of action studies also demonstrated that 6a-9 displays the effects in both the early and late stages of HIV-1 replication. To explore the potential binding mode of the here presented analogues, 6a-9 was analyzed by MD simulation to predict its binding to the active site of HIV-1 CA monomer. In conclusion, this novel series of antivirals can serve as a starting point for the development of a new generation of HIV-1 treatment regimen and highlights the potentiality of CA as a therapeutic target.

更新日期：2020-01-24

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