Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from Prorocentrum lima PL11: Isolation, Structural Modification, and Mechanistic Study

文献类型： 外文期刊

第一作者： Huang, Dong

作者： Huang, Dong;Yuan, Fang-Yu;Wu, Shu-Qi;Weng, Han-Zhuang;Tang, Gui-Hua;Yin, Sheng;Ding, Lian-Shuai;Gao, Xiang;Ding, Lian-Shuai;Tian, Xiao-Qing;Fan, Cheng-Qi

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关键词： marine toxins; okadaic acid; Prorocentrum lima PL11; structural modification; HIV latency reversal activity

期刊名称：MARINE DRUGS （ 影响因子：5.4； 五年影响因子：5.5 ）

ISSN：

年卷期： 2023 年 21 卷 3 期

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收录情况： SCI

摘要： 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) (1) and OA methyl ester (2), were isolated from the cultured microalgae strain Prorocentrum lima 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 (3) and four new derivatives (4-7). Flow cytometry-based HIV latency reversal activity screening showed that compound 7 possessed a stronger activity (EC50 = 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 7 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.

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