| Autor: |
Huang D; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China., Ding LS; State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.; School of Life Sciences, Xiamen University, Xiamen 361102, China., Yuan FY; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China., Wu SQ; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China., Weng HZ; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China., Tian XQ; East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China., Tang GH; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China., Fan CQ; East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China., Gao X; State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China., Yin S; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. |
| Abstrakt: |
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 (EC 50 = 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. |
