Wikstroelide M potently inhibits HIV replication by targeting reverse transcriptase and integrase nuclear translocation.
10.1016/S1875-5364(14)60031-5
- Author:
Xuan ZHANG
1
,
2
;
Sheng-Zhuo HUANG
3
;
Wan-Gang GU
4
;
Liu-Meng YANG
5
;
Huan CHEN
5
;
Chang-Bo ZHENG
6
;
You-Xing ZHAO
3
;
David Chi-Cheong WAN
4
;
Yong-Tang ZHENG
7
Author Information
1. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
2. School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China.
3. Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China.
4. School of Biomedical Sciences, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China.
5. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
6. School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
7. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China. Electronic address: zhengyt@mail.kiz.ac.cn.
- Publication Type:Journal Article
- Keywords:
Daphnane diterpene;
Daphne acutiloba Rehder;
HIV;
Lens epithelium-derived growth factor (LEDGF/p75);
Molecular docking;
Nuclear translocation;
Reverse trascriptase;
Wikstroelide M;
integrase
- MeSH:
Anti-HIV Agents;
pharmacology;
therapeutic use;
Cell Line;
Daphne;
chemistry;
Diterpenes;
pharmacology;
HIV Infections;
drug therapy;
virology;
HIV Integrase;
metabolism;
HIV Integrase Inhibitors;
pharmacology;
therapeutic use;
HIV Reverse Transcriptase;
antagonists & inhibitors;
HIV-1;
drug effects;
enzymology;
HIV-2;
drug effects;
Humans;
Intercellular Signaling Peptides and Proteins;
metabolism;
Phytotherapy;
Plant Extracts;
pharmacology;
therapeutic use;
Virus Integration;
drug effects;
Virus Replication;
drug effects
- From:
Chinese Journal of Natural Medicines (English Ed.)
2014;12(3):186-193
- CountryChina
- Language:English
-
Abstract:
AIM:To evaluate the anti-HIV activity and mechanism of action of wikstroelide M, a daphnane diterpene from Daphne acutiloba Rehder (Thymelaeaceae).
METHODS:The anti-HIV activities of wikstroelide M against different HIV strains were evaluated by cytopathic effect assay and p24 quantification assay with ELISA. The inhibitory effect of wikstroelide M on HIV reverse transcription was analyzed by real-time PCR and ELISA. The effect of wikstroelide M on HIV-1 integrase nuclear translocation was observed with a cell-based imaging assay. The effect of wikstroelide M on LEDGF/p75-IN interaction was assayed by molecular docking.
RESULTS:Wikstroelide M potently inhibited different HIV-1 strains, including HIV-1IIIB, HIV-1A17, and HIV-19495, induced a cytopathic effect, with EC50 values ranging from 3.81 to 15.65 ng·mL⁻¹. Wikstroelide M also had high inhibitory activities against HIV-2ROD and HIV-2CBL-20-induced cytopathic effects with EC50 values of 18.88 and 31.90 ng·mL⁻¹. The inhibitory activities of wikstroelide M on the three HIV-1 strains were further confirmed by p24 quantification assay, with EC50 values ranging from 15.16 to 35.57 ng·mL⁻¹. Wikstroelide M also potently inhibited HIV-1IIIB induced cytolysis in MT-4 cells, with an EC50 value of 9.60 ng·mL⁻¹. The mechanistic assay showed that wikstroelide M targeted HIV-1 reverse transcriptase and nuclear translocation of integrase through disrupting the interaction between integrase and LEDGF/p75.
CONCLUSION:Wikstroelide M may be a potent HIV-1 and HIV-2 inhibitor, the mechanisms of action may include inhibition of reverse trascriptase activity and inhibition of integrase nuclear translocation through disrupting the interaction between integrase and LEDGF/p75.
