Anti-HIV Effects of Baculiferins Are Regulated by the Potential Target Protein DARS.
Anti-HIV Effects of Baculiferins Are Regulated by the Potential Target Protein DARS.
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DOI：
10.1021/acschembio.1c00148
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发表时间：
2021-08
影响因子：
4
通讯作者：
Jianrong Liu;Ling Ma;C. Song;H. Xing;S. Cen;Wenhan Lin
中科院分区：
文献类型：
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作者：
Jianrong Liu;Ling Ma;C. Song;H. Xing;S. Cen;Wenhan Lin
芽孢杆菌毒素是一类从海绵中提取的具有抗HIV(人类免疫缺陷病毒)活性的多环生物碱。为了确定更多的杆状杆菌红素同系物用于合成孔径雷达分析，并研究其作用机制，我们合成了18个新的杆状杆菌红素类化合物。对化合物的体外抗HIV-1活性进行了评价，并对相关的SAR进行了讨论。化合物18在体外对VSv-G假型HIV-1和HIV-1 SF33株的IC50值分别为3.44μM和2.80μM。为了识别细胞靶点，同时合成了三个光亲和杆状病毒蛋白探针。光亲和标记实验结合LC-MS/MS数据确定天冬氨酸-tRNA连接酶(DARS)是一个推测为18的靶蛋白。DARS在HEK293T细胞中的过表达和敲除为进一步证明DARS是一个潜在的调控HIV病毒感染的靶蛋白提供了进一步的资料。通过分子对接模拟确定了抗病毒杆状病毒蛋白13和18与DARS的结合方式。因此，杆状杆菌凝集素18被认为是一个很有前途的先导分子，可以作为抗HIV药物开发的新分子靶点。
Baculiferins are a group of marine sponge-derived polycyclic alkaloids with anti-HIV (human immunodeficiency virus) activities. To identify additional baculiferin-based congeners for SAR analysis and to investigate the mode of action, a total of 18 new baculiferin-type derivatives were synthesized. The inhibitory activities of the congeners against the HIV-1 virus were evaluated in vitro, and the relevant SAR was discussed. Compound 18 exerted the most potent activity toward VSV-G-pseudotyped HIV-1 (IC50 of 3.44 μM) and HIV-1 strain SF33 (IC50 of 2.80 μM) in vitro. To identify the cellular targets, three photoaffinity baculiferin probes were simultaneously synthesized. Photoaffinity labeling experiments together with LC-MS/MS data identified aspartate-tRNA ligase (DARS) as a putative target protein of 18. The overexpression and knockdown of DARS in HEK293T cells provided additional data to demonstrate that DARS is a potential target protein in the regulation of HIV virus infection. The modes of antiviral baculiferins 13 and 18 binding to DARS were determined by a molecular docking simulation. Thus, baculiferin 18 is considered a promising lead as a new molecular target for the development of anti-HIV agents.