Design, synthesis, and biological evaluation of novel AAK1/HDACs dual inhibitors against SARS-CoV-2 entry.

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-19 DOI:10.1016/j.bioorg.2024.107973
Nian-Dong Mao, Yueying Xu, Xia Yao, Yuan Gao, Zi Hui, Hao Che, Chenchen Wang, Jinshan Lu, Jie Yu, Suwen Hu, Hang Zhang, Xiang-Yang Ye
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Abstract

AP2-associated protein kinase 1 (AAK1) is a crucial regulator of clathrin-mediated endocytosis, involved in various cellular processes, including viral infection. Histone deacetylases (HDACs) are essential in regulating gene transcription through the process of histone deacetylation and have become promising therapeutic targets for the treatment of cancer and viral infections. In this study, several AAK1/HDACs dual inhibitors based on our previous reported compounds were designed and synthesized, and the antiviral activity of these dual inhibitors were evaluated. Among them, compound 12 showed remarkable dual inhibitory activity against both AAK1 and HDACs, with IC50 values of 15.9 nM for AAK1, 148.7 nM for HDAC1, and 5.2 nM for HDAC6. Notably, this compound exhibited superior efficacy in suppressing SARS-CoV-2 entry into host cells compared to its close analogs 4, 13a, and 13b. Mechanistically, compound 12 attenuated AAK1-induced phosphorylation of adaptor protein-2 μ subunit (AP2M1) threonine 156, disrupting the direct interaction between AP2M1 and ACE2, thus inhibiting the CME-mediated SARS-CoV-2 endocytosis. Additionally, compound 12 increased the acetylation levels of H3K27 and α-tubulin, suggesting its potential as an epigenetic modulator. Overall, our findings propose compound 12 as a promising dual inhibitor against AAK1 and HDACs, highlighting its therapeutic potential in antiviral infections.

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新型 AAK1/HDACs 双抑制剂的设计、合成和生物学评价,对抗 SARS-CoV-2 进入。
AP2相关蛋白激酶1(AAK1)是凝集素介导的内吞作用的重要调节因子,参与包括病毒感染在内的各种细胞过程。组蛋白去乙酰化酶(HDAC)通过组蛋白去乙酰化过程调节基因转录,已成为治疗癌症和病毒感染的有前途的治疗靶标。本研究在之前报道的化合物基础上,设计合成了几种 AAK1/HDACs 双重抑制剂,并对这些双重抑制剂的抗病毒活性进行了评估。其中,化合物 12 对 AAK1 和 HDACs 都表现出了显著的双重抑制活性,对 AAK1 的 IC50 值为 15.9 nM,对 HDAC1 的 IC50 值为 148.7 nM,对 HDAC6 的 IC50 值为 5.2 nM。值得注意的是,与近似的类似物 4、13a 和 13b 相比,该化合物在抑制 SARS-CoV-2 进入宿主细胞方面表现出更强的功效。从机理上讲,化合物 12 削弱了 AAK1 诱导的适配蛋白-2 μ 亚基(AP2M1)苏氨酸 156 磷酸化,破坏了 AP2M1 和 ACE2 之间的直接相互作用,从而抑制了 CME 介导的 SARS-CoV-2 内吞。此外,化合物 12 还增加了 H3K27 和 α-tubulin的乙酰化水平,表明其具有作为表观遗传调节剂的潜力。总之,我们的研究结果表明化合物 12 是一种很有前景的 AAK1 和 HDAC 双重抑制剂,凸显了它在抗病毒感染方面的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Bioorganic Chemistry
Bioorganic Chemistry 生物-生化与分子生物学
CiteScore
9.70
自引率
3.90%
发文量
679
审稿时长
31 days
期刊介绍: Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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