Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from Prorocentrum lima PL11:...

Area of Science:

• Natural Product Chemistry
• Virology
• Medicinal Chemistry

Background:

• Marine toxins (MTs) are complex natural products with diverse bioactivities.
• Okadaic acid (OA), a marine toxin, activates latent HIV but exhibits significant toxicity.
• Developing safer and more effective HIV latency reversing agents (LRAs) is crucial.

Purpose of the Study:

• To synthesize novel okadaic acid derivatives as potential LRAs.
• To evaluate the anti-HIV latency activity and cytotoxicity of these derivatives.
• To elucidate the mechanism of action for promising compounds.

Main Methods:

• Isolation of okadaic acid and its methyl ester from *Prorocentrum lima*.
• Structural modification of okadaic acid via esterification to create new derivatives.
• Flow cytometry-based screening for HIV latency reversal activity and cytotoxicity assays.

Main Results:

• Four new okadaic acid derivatives were synthesized, along with one known compound.
• Compound 7 demonstrated enhanced HIV latency reversal activity (EC50 = 46 ± 13.5 nM) and reduced cytotoxicity compared to OA.
• Structure-activity relationship studies indicated the importance of the carboxyl group and benefits of esterification for reduced toxicity.

Conclusions:

• Compound 7 represents a promising candidate for an HIV LRA with improved tolerability.
• Structural modifications of marine toxins can yield potent therapeutic agents.
• Compound 7's mechanism involves promoting P-TEFb dissociation from the 7SK snRNP complex, reactivating HIV-1.