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.

中文翻译：

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杆状蛋白的抗 HIV 作用受潜在靶蛋白 DARS 的调节

Baculiferins 是一组源自海绵的多环生物碱，具有抗 HIV（人类免疫缺陷病毒）活性。为了确定用于 SAR 分析的其他杆状杆蛋白同系物并研究作用模式，共合成了 18 种新的杆状杆状蛋白型衍生物。体外评价了同源物对HIV-1病毒的抑制活性，并讨论了相关的SAR。化合物18在体外对 VSV-G 假型 HIV-1（IC ₅₀为 3.44 μM）和 HIV-1 毒株 SF33（IC ₅₀为 2.80 μM）发挥最有效的活性. 为了识别细胞靶标，同时合成了三种光亲和杆状蛋白探针。光亲和标记实验连同 LC-MS/MS 数据将天冬氨酸-tRNA 连接酶 (DARS) 鉴定为推定的目标蛋白18。HEK293T 细胞中 DARS 的过表达和敲低提供了额外的数据，以证明 DARS 是调节 HIV 病毒感染的潜在靶蛋白。通过分子对接模拟确定了抗病毒杆状蛋白13和18与 DARS 结合的模式。因此，杆状蛋白18被认为是开发抗 HIV 药物的新分子靶标的有前景的先导物。