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

• Published in: Marine drugs 2023-02, Vol.21 (3), p.158
• Main Authors: Huang, Dong, Ding, Lian-Shuai, Yuan, Fang-Yu, Wu, Shu-Qi, Weng, Han-Zhuang, Tian, Xiao-Qing, Tang, Gui-Hua, Fan, Cheng-Qi, Gao, Xiang, Yin, Sheng
• Format: Article
• Language: English
• Subjects: Acids; Acquired immune deficiency syndrome; AIDS; Algae; Alzheimers disease; Carboxyl group; Cell cycle; Cytotoxicity; Dinoflagellida - chemistry; Dissociation; Esterification; Flow cytometry; HIV; HIV Infections; HIV latency reversal activity; HIV-1; Human immunodeficiency virus; Humans; Latency; Lymphoma; marine toxins; Marine Toxins - chemistry; Metabolites; Metastasis; Natural products; Okadaic acid; Okadaic Acid - toxicity; Phosphatase; Phytoplankton; Prorocentrum lima; Prorocentrum lima PL11; Proteins; Ribonucleoproteins (small nuclear); Shellfish; structural modification; Toxicity; Toxins; Virus Latency
• ISSN: 1660-3397; 1660-3397
• 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.