Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from <i>Prorocentrum lima</i> PL11: Isolation, Structural Modification, and Mechanistic Study
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) (<b>1</b>) and OA methyl ester (<b>2</b>), were isolated from the cultured m...
| Main Authors: | , , , , , , , , , |
|---|---|
| 格式: | Article |
| 語言: | English |
| 出版: |
MDPI AG
2023-02-01
|
| 叢編: | Marine Drugs |
| 主題: | |
| 在線閱讀: | https://www.mdpi.com/1660-3397/21/3/158 |
| _version_ | 1827748964528553984 |
|---|---|
| author | Dong Huang Lian-Shuai Ding Fang-Yu Yuan Shu-Qi Wu Han-Zhuang Weng Xiao-Qing Tian Gui-Hua Tang Cheng-Qi Fan Xiang Gao Sheng Yin |
| author_facet | Dong Huang Lian-Shuai Ding Fang-Yu Yuan Shu-Qi Wu Han-Zhuang Weng Xiao-Qing Tian Gui-Hua Tang Cheng-Qi Fan Xiang Gao Sheng Yin |
| author_sort | Dong Huang |
| collection | DOAJ |
| description | 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) (<b>1</b>) and OA methyl ester (<b>2</b>), were isolated from the cultured microalgae strain <i>Prorocentrum lima</i> 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 (<b>3</b>) and four new derivatives (<b>4</b>–<b>7</b>). Flow cytometry-based HIV latency reversal activity screening showed that compound <b>7</b> possessed a stronger activity (EC<sub>50</sub> = 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 <b>7</b> 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. |
| first_indexed | 2024-03-11T06:16:17Z |
| format | Article |
| id | doaj.art-6b4daa21c32f4a6f9a94c20cc1b3c84c |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-03-11T06:16:17Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-6b4daa21c32f4a6f9a94c20cc1b3c84c2023-11-17T12:17:21ZengMDPI AGMarine Drugs1660-33972023-02-0121315810.3390/md21030158Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from <i>Prorocentrum lima</i> PL11: Isolation, Structural Modification, and Mechanistic StudyDong Huang0Lian-Shuai Ding1Fang-Yu Yuan2Shu-Qi Wu3Han-Zhuang Weng4Xiao-Qing Tian5Gui-Hua Tang6Cheng-Qi Fan7Xiang Gao8Sheng Yin9Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaState Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, ChinaSouthern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSouthern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSouthern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaEast China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, ChinaSouthern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaEast China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, ChinaState Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, ChinaSouthern Marine Science and Engineering Guangdong Laboratory (Zhuhai), School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaMarine 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) (<b>1</b>) and OA methyl ester (<b>2</b>), were isolated from the cultured microalgae strain <i>Prorocentrum lima</i> 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 (<b>3</b>) and four new derivatives (<b>4</b>–<b>7</b>). Flow cytometry-based HIV latency reversal activity screening showed that compound <b>7</b> possessed a stronger activity (EC<sub>50</sub> = 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 <b>7</b> 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.https://www.mdpi.com/1660-3397/21/3/158marine toxinsokadaic acid<i>Prorocentrum lima</i> PL11structural modificationHIV latency reversal activity |
| spellingShingle | Dong Huang Lian-Shuai Ding Fang-Yu Yuan Shu-Qi Wu Han-Zhuang Weng Xiao-Qing Tian Gui-Hua Tang Cheng-Qi Fan Xiang Gao Sheng Yin Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from <i>Prorocentrum lima</i> PL11: Isolation, Structural Modification, and Mechanistic Study Marine Drugs marine toxins okadaic acid <i>Prorocentrum lima</i> PL11 structural modification HIV latency reversal activity |
| title | Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from <i>Prorocentrum lima</i> PL11: Isolation, Structural Modification, and Mechanistic Study |
| title_full | Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from <i>Prorocentrum lima</i> PL11: Isolation, Structural Modification, and Mechanistic Study |
| title_fullStr | Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from <i>Prorocentrum lima</i> PL11: Isolation, Structural Modification, and Mechanistic Study |
| title_full_unstemmed | Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from <i>Prorocentrum lima</i> PL11: Isolation, Structural Modification, and Mechanistic Study |
| title_short | Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from <i>Prorocentrum lima</i> PL11: Isolation, Structural Modification, and Mechanistic Study |
| title_sort | discovering a new okadaic acid derivative a potent hiv latency reversing agent from i prorocentrum lima i pl11 isolation structural modification and mechanistic study |
| topic | marine toxins okadaic acid <i>Prorocentrum lima</i> PL11 structural modification HIV latency reversal activity |
| url | https://www.mdpi.com/1660-3397/21/3/158 |
| work_keys_str_mv | AT donghuang discoveringanewokadaicacidderivativeapotenthivlatencyreversingagentfromiprorocentrumlimaipl11isolationstructuralmodificationandmechanisticstudy AT lianshuaiding discoveringanewokadaicacidderivativeapotenthivlatencyreversingagentfromiprorocentrumlimaipl11isolationstructuralmodificationandmechanisticstudy AT fangyuyuan discoveringanewokadaicacidderivativeapotenthivlatencyreversingagentfromiprorocentrumlimaipl11isolationstructuralmodificationandmechanisticstudy AT shuqiwu discoveringanewokadaicacidderivativeapotenthivlatencyreversingagentfromiprorocentrumlimaipl11isolationstructuralmodificationandmechanisticstudy AT hanzhuangweng discoveringanewokadaicacidderivativeapotenthivlatencyreversingagentfromiprorocentrumlimaipl11isolationstructuralmodificationandmechanisticstudy AT xiaoqingtian discoveringanewokadaicacidderivativeapotenthivlatencyreversingagentfromiprorocentrumlimaipl11isolationstructuralmodificationandmechanisticstudy AT guihuatang discoveringanewokadaicacidderivativeapotenthivlatencyreversingagentfromiprorocentrumlimaipl11isolationstructuralmodificationandmechanisticstudy AT chengqifan discoveringanewokadaicacidderivativeapotenthivlatencyreversingagentfromiprorocentrumlimaipl11isolationstructuralmodificationandmechanisticstudy AT xianggao discoveringanewokadaicacidderivativeapotenthivlatencyreversingagentfromiprorocentrumlimaipl11isolationstructuralmodificationandmechanisticstudy AT shengyin discoveringanewokadaicacidderivativeapotenthivlatencyreversingagentfromiprorocentrumlimaipl11isolationstructuralmodificationandmechanisticstudy |