Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
Mar Drugs. 2023 Feb 27;21(3):158. doi: 10.3390/md21030158.
Marine toxins (MTs) are a group of structurally complex natural products with unique toxicological and pharmacological activities. In the present study, two common shellfish toxins, okadaic acid (OA) () and OA methyl ester (), were isolated from the cultured microalgae strain PL11. OA can significantly activate the latent HIV but has severe toxicity. To obtain more tolerable and potent latency reversing agents (LRAs), we conducted the structural modification of OA by esterification, yielding one known compound () and four new derivatives (-). Flow cytometry-based HIV latency reversal activity screening showed that compound possessed a stronger activity (EC = 46 ± 13.5 nM) but was less cytotoxic than OA. The preliminary structure-activity relationships (SARs) indicated that the carboxyl group in OA was essential for activity, while the esterification of carboxyl or free hydroxyls were beneficial for reducing cytotoxicity. A mechanistic study revealed that compound promotes the dissociation of P-TEFb from the 7SK snRNP complex to reactivate latent HIV-1. Our study provides significant clues for OA-based HIV LRA discovery.
海洋毒素 (MTs) 是一组结构复杂的天然产物，具有独特的毒理学和药理学活性。在本研究中，从培养的微藻菌株 PL11 中分离出两种常见的贝类毒素，冈田酸 (OA) () 和 OA 甲酯 ()。OA 可显著激活潜伏的 HIV，但毒性很强。为了获得更耐受和有效的潜伏逆转剂 (LRA)，我们通过酯化对 OA 进行了结构修饰，得到了一个已知化合物 () 和四个新衍生物 (-)。基于流式细胞术的 HIV 潜伏逆转活性筛选表明，化合物 具有更强的活性 (EC = 46 ± 13.5 nM)，但比 OA 的细胞毒性更小。初步的构效关系 (SAR) 表明，OA 中的羧基对于活性是必需的，而羧基或游离羟基的酯化有利于降低细胞毒性。一项机制研究表明，化合物 促进 P-TEFb 从 7SK snRNP 复合物中解离，从而重新激活潜伏的 HIV-1。我们的研究为基于 OA 的 HIV LRA 发现提供了重要线索。
