青蒿素抗瘧機理的化學生物學研究進展

1、青蒿素抗瘧機理的化學生物學研究進展王繼剛新加坡國立大學藥理系 117597 瘧疾是一種由瘧原蟲感染引起的，嚴重威脅人類健康和生命安全的重大傳染病, 在全世界108個國家和地區(qū)傳播流行, 約有33億人受到瘧疾的威脅, 每年有超過1億人感染瘧疾, 并造成近80萬人死亡。瘧疾也曾在我國大規(guī)模流行, 但經過多年的積極防治, 我國瘧疾疫情已大規(guī)模下降, 發(fā)病人數從建國初期每年3000萬下降至2010 年的每年7000 多例。世界衛(wèi)生組織（World Health Organization, WHO）將瘧疾與艾滋病、結核病一起列為全球三大公共衛(wèi)生問題。青蒿素是中國科學家屠呦呦及其研究團隊從黃花蒿中分離得到

2、的抗瘧藥物, 在全世界治療瘧疾的過程中發(fā)揮了重要作用。隨著屠呦呦2015年獲得諾貝爾生理學或醫(yī)學獎, 青蒿素的研究再次成為熱點。但是其具體的抗瘧活性作用機制并不明確。青蒿素的作用機制非常復雜, 尤其是其激活過程。最近, 隨著化學生物學平臺在青蒿素作用機制研究中的應用, 青蒿素研究有了新的突破。作者所在實驗室及合作者運用化學生物學的方法，于近期確定了青蒿素必須在瘧原蟲降解血紅蛋白的副產物-血紅素的作用下才能被激活，隨后共價結合一系列的寄生蟲蛋白，從而快速殺死瘧原蟲。作者也發(fā)現青蒿素在瘧原蟲不同生活周期的激活程度和靶標差異非常巨大，并且抗瘧瘧原蟲的細胞周期分化情況與敏感瘧原蟲相比也發(fā)生了顯著地差異

3、。以上結果，對研究瘧原蟲對青蒿素的抗藥性有著重要的指導作用。The recent progress of chemical biology in artemisinin mechanism researchWANG JigangDepartment of Pharmacology, National University of Singapore, Singapore 117597, Singapore王繼剛, E-mail: Artemisinin is the active principle extract of sweet wormwood, Artemisia annua which

4、 is used to relieve pain and fever in the older days. Today, artemisinin is widely used as an anti-malarial drug as our first line of defense to combat the emergence of drug resistance malaria parasite. Besides its anti-malarial properties, artemisinin is being investigated in other diseases. It is

5、found to possess a wide spectrum of pharmacological activities, including anticancer, anti-asthma etc. However, its mechanism of action (MOA) is still not fully understood. Recently, chemical proteomics approach has been used in identify the targets and unravel the mechanism of action of artemisinin

6、. In this talk, I will briefly summarize the recent advances of chemical biology in artemisinin target and mechanism study.近5年內代表性論文: (   共同通訊作者，#共同第一作者)1. Wong YK#, Zhang JB#, Hua ZC, Lin QS, Shen HM*, Wang JG*.(2017) Recent Advances in Quantitative and Chemical Protoemics for Autophagy Studie

7、s. Autophagy. 13, 1472-1486. 2. Wong YK, Xu CC, Kalesh KA, He YK, Lin QS, Wong WS*, Shen HM*, Wang JG*. (2017) Artemisinin as an Anti-Cancer Drug: Recent Advances in Target Profiling and Mechanisms of Action. Medicinal Research Reviews, 37, 1492-1517. 3. Wang JG#*, Zhang CJ#, Chia WN, Loh CCY, Li ZJ

8、, Lee YM, He YK, Yuan LX, Lim TK, Liu M, Liew CX, Lee YQ, Zhang JB, Lu NC, Lim CT, Hua ZC, Shen HM, Tan KSW*, Lin QS*. (2015) Haem-activated Promiscuous Targeting of Artemisinin in Plasmodium falciparum. Nature Communications, 6:10111. (Faculty of 1000 recommended as being of exceptional signif

9、icance; Highlighted in ACS Chemical and Engineering News; Highlighted in NatureAsia; Highlighted in ACS Chemical Biology; Highly cited paper in the field of Biology & Biochemistry in 2016)4. Wang JG#, Zhang JB#, Lee YM, Ng S, Shi Y, Hua Z-C, Lin QS, Shen HM. (2017). Nonradioactive

10、 quantification of autophagic protein degradation with L-azidohomoalanine labelling. Nature Protocols, 12, 279-288. 5. Wang JG#*, Zhang JB#, Shi Y#, Xu CC#, Zhang CJ, Wong YK, Lee YM, Krishna S, He YK, Lim TK, Liu B, Hua ZC, Shen HM*, Lin QS*. (2017). Mechanistic Investigation of the Specific Antica

11、ncer Property of Artemisinin and Its Combination with Aminolevulinic Acid for Enhanced Anti-colorectal Cancer Activity. ACS Central Sciences, 3, 743-750. (Cover story of the issue)6. Zhang CJ#, Wang JG#*, Zhang JB, Lee YM, Feng GX, Lim TK, Shen H-M, Lin QS*, Liu B*. (#equal contribution). (2016) Mec

12、hanism-Guided Design and Synthesis of Mitochondria- targeting Artemisinin Analog with Enhanced Anticancer Activity. Angew. Chem. Int. Ed., 55, 13770-13774. 7. Wang JG#*, Xu CC#, Lun ZR*, Meshnick SR. (2017) Unpacking “Artemisinin Resistance”. Trends in Pharmacological Sciences, 38, 506-511 8. Wang J

13、G#*, Gao LQ#, Lee YM#, Kalesh KA, Ong YS, Lim J, Lee JE, Sun HY, Lee SS*, Hua ZC*, Lin QS*. (2016) Target identification of natural and traditional medicines with quantitative chemical proteomics approaches. Pharmacology & Theraputics, 162, 10-22. 9. Zhang JB#, Wang JG#, Zhou ZH, Zhang CJ, Eun P

14、J, Wu S, Sze SK, Lin QS, Shen HM. (2017) Acetylation of TFEB activates lysosomal function in response to histone deacetylase inhibitor SAHA treatment. Autophagy, 10.1080/15548627.2018.1447290. 10. Wang JG#, Zhang JB#, Lee YM, Koh PL, Ng SK, Bao FC, Hua ZC, Lin QS*, Shen HM*. (2016). Quantitative Che

15、mical Proteomics Profiling of de novo Proteins Synthesis during Starvation-Mediated Autophagy, Autophagy, 12, 1931-1944. 11. Zhang JB#, Wang JG#, Ng S, Lin QS*, Shen HM*. (2014). Development of a novel method for quantification of autophagic protein degradation by AHA labeling. Autophagy, 10, 901-91

16、2. 12. Chen X, Li W, Xu CC, Wang J, Zhu B, Huang Q, Chen D, Sheng J, Zou Y, Lee YM, Tan RX, Shen P, Wong YK, Lin Q, Wang JG*, Hua ZC*. (2018). Comparative profiling of analog targets: a case study on resveratrol for mouse melanoma metastasis suppression. Theranostics, in press. 13. Wang JG#, Tan XF#

17、, NguyenVS, Yang P, Zhou J, Gao MM, Li ZJ, Lim TK, He YK, Ong CS, Lay YF, Zhang JB, Zhu GL, Lai SL, Ghosh D, Mok YK, Shen HM, Lin QS. (2014). A Quantitative Chemical Proteomics Approach to Pro Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent that Suppresses Tumor Metastasis. Molecular & Cellular Proteomics, 13, 876-886. 14. Wang JG*#, Wong YK#, Zhang JB#, Lee YM, Hua ZC*, Shen HM*, Lin QS*. (2017). Drug Target Identification using an iTRAQ-Based Quantitative Chemical Proteomics Approac