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发现新型 1,2,4-三唑苯丙氨酸衍生物，靶向 HIV 衣壳蛋白互变异构口袋内未探索区域。

Discovery of novel 1,2,4-triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein.

机构信息

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi, India.

出版信息

J Med Virol. 2022 Dec;94(12):5975-5986. doi: 10.1002/jmv.28064. Epub 2022 Aug 18.

DOI:10.1002/jmv.28064
PMID:35949003
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10790228/
Abstract

Human immunodeficiency virus (HIV) capsid (CA) protein is a promising target for developing novel anti-HIV drugs. Starting from highly anticipated CA inhibitors PF-74, we used scaffold hopping strategy to design a series of novel 1,2,4-triazole phenylalanine derivatives by targeting an unexplored region composed of residues 106-109 in HIV-1 CA hexamer. Compound d19 displayed excellent antiretroviral potency against HIV-1 and HIV-2 strains with EC values of 0.59 and 2.69 µM, respectively. Additionally, we show via surface plasmon resonance (SPR) spectrometry that d19 preferentially interacts with the hexameric form of CA, with a significantly improved hexamer/monomer specificity ratio (ratio = 59) than PF-74 (ratio = 21). Moreover, we show via SPR that d19 competes with CPSF-6 for binding to CA hexamers with IC value of 33.4 nM. Like PF-74, d19 inhibits the replication of HIV-1 NL4.3 pseudo typed virus in both early and late stages. In addition, molecular docking and molecular dynamics simulations provide binding mode information of d19 to HIV-1 CA and rationale for improved affinity and potency over PF-74. Overall, the lead compound d19 displays a distinct chemotype form PF-74, improved CA affinity, and anti-HIV potency.

摘要

人类免疫缺陷病毒 (HIV) 衣壳 (CA) 蛋白是开发新型抗 HIV 药物的有前途的靶标。我们从备受期待的 CA 抑制剂 PF-74 出发，通过针对 HIV-1 CA 六聚体中由残基 106-109 组成的未探索区域，使用支架跳跃策略设计了一系列新型 1,2,4-三唑苯丙氨酸衍生物。化合物 d19 对 HIV-1 和 HIV-2 株具有出色的抗逆转录病毒活性，EC 值分别为 0.59 和 2.69µM。此外，我们通过表面等离子体共振 (SPR) 光谱法表明，d19 优先与 CA 的六聚体形式相互作用，与 PF-74（比值=21）相比，六聚体/单体特异性比值（比值=59）显著提高。此外，我们通过 SPR 表明，d19 与 CPSF-6 竞争与 CA 六聚体的结合，IC 值为 33.4nM。与 PF-74 一样，d19 抑制 HIV-1 NL4.3 假型病毒在早期和晚期的复制。此外，分子对接和分子动力学模拟提供了 d19 与 HIV-1 CA 的结合模式信息，并解释了其对 PF-74 的亲和力和效力提高的原因。总的来说，先导化合物 d19 显示出与 PF-74 不同的化学类型，提高了 CA 的亲和力和抗 HIV 效力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/58cd/10790228/8a0e0d560d38/nihms-1829759-f0009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/58cd/10790228/8a0e0d560d38/nihms-1829759-f0009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/58cd/10790228/fc89a6b418a9/nihms-1829759-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/58cd/10790228/29b1ec5a5db2/nihms-1829759-f0007.jpg
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