青蒿素抗疟机理的化学生物学研究进展

青蒿素抗疟机理的化学生物学研究进展王继刚新加坡国立大学药理系117597疟疾是一种由疟原虫感染引起的，严重威胁人类健康和生命安全的重大传染病,在全世界108个国家和地区传播流行,约有33亿人受到疟疾的威胁,每年有超过1亿人感染疟疾,并造成近80万人死亡。疟疾也曾在我国大规模流行,但经过多年的积极防治,我国疟疾疫情已大规模下降,发病人数从建国初期每年3000万下降至2010年的每年7000多例。世界卫生组织（WorldHealthOrganization,WHO）将疟疾与艾滋病、结核病一起列为全球三大公共卫生问题。青蒿素是中国科学家屠呦呦及其研究团队从黄花蒿中分离得到的抗疟药物,在全世界治疗疟疾的过程中发挥了重要作用。随着屠呦呦2015年获得诺贝尔生理学或医学奖,青蒿素的研究再次成为热点。但是其具体的抗疟活性作用机制并不明确。青蒿素的作用机制非常复杂,尤其是其激活过程。最近,随着化学生物学平台在青蒿素作用机制研究中的应用,青蒿素研究有了新的突破。作者所在实验室及合作者运用化学生物学的方法，于近期确定了青蒿素必须在疟原虫降解血红蛋白的副产物-血红素的作用下才能被激活，随后共价结合一系列的寄生虫蛋白，从而快速杀死疟原虫。作者也发现青蒿素在疟原虫不同生活周期的激活程度和靶标差异非常巨大，并且抗疟疟原虫的细胞周期分化情况与敏感疟原虫相比也发生了显著地差异。以上结果，对研究疟原虫对青蒿素的抗药性有着重要的指导作用。 TherecentprogressofchemicalbiologyinartemisininmechanismresearchWANGJigangDepartmentofPharmacology,NationalUniversityofSingapore,Singapore117597,Singapore王继刚,E-mail:wangjigang@u.nus.eduArtemisininistheactiveprincipleextractofsweetwormwood,Artemisiaannuawhichisusedtorelievepainandfeverintheolderdays.Today,artemisininiswidelyusedasananti-malarialdrugasourfirstlineofdefensetocombattheemergenceofdrugresistancemalariaparasite.Besidesitsanti-malarialproperties,artemisininisbeinginvestigatedinotherdiseases.Itisfoundtopossessawidespectrumofpharmacologicalactivities,includinganticancer,anti-asthmaetc.However,itsmechanismofaction(MOA)isstillnotfullyunderstood.Recently,chemicalproteomicsapproachhasbeenusedinidentifythetargetsandunravelthemechanismofactionofartemisinin.Inthistalk,Iwillbrieflysummarizetherecentadvancesofchemicalbiologyinartemisinintargetandmechanismstudy. 近5年内代表性论文:( ⃰共同通讯作者，#共同第一作者)1.WongYK#,ZhangJB#,HuaZC,LinQS,ShenHM*,WangJG*.(2017)RecentAdvancesinQuantitativeandChemicalProtoemicsforAutophagyStudies.Autophagy.13,1472-1486.2.WongYK,XuCC,KaleshKA,HeYK,LinQS,WongWS*,ShenHM*,WangJG*.(2017)ArtemisininasanAnti-CancerDrug:RecentAdvancesinTargetProfilingandMechanismsofAction.MedicinalResearchReviews,37,1492-1517.3.WangJG#*,ZhangCJ#,ChiaWN,LohCCY,LiZJ,LeeYM,HeYK,YuanLX,LimTK,LiuM,LiewCX,LeeYQ,ZhangJB,LuNC,LimCT,HuaZC,ShenHM,TanKSW*,LinQS*.(2015)Haem-activatedPromiscuousTargetingofArtemisinininPlasmodiumfalciparum.NatureCommunications,6:10111.(Facultyof1000 recommendedasbeingofexceptionalsignificance;Highlighted inACSChemicalandEngineeringNews;Highlighted inNatureAsia;HighlightedinACSChemicalBiology;Highlycitedpaperinthefieldof Biology&Biochemistryin2016)4.WangJG#,ZhangJB#,LeeYM,NgS,ShiY,HuaZ-C,LinQS,ShenHM.(2017).NonradioactivequantificationofautophagicproteindegradationwithL-azidohomoalaninelabelling.NatureProtocols,12,279-288.5.WangJG#*,ZhangJB#,ShiY#,XuCC#,ZhangCJ,WongYK,LeeYM,KrishnaS,HeYK,LimTK,LiuB,HuaZC,ShenHM*,LinQS*.(2017).MechanisticInvestigationoftheSpecificAnticancerPropertyofArtemisininandItsCombinationwithAminolevulinicAcidforEnhancedAnti-colorectalCancerActivity.ACSCentralSciences,3,743-750.(Coverstoryoftheissue)6.ZhangCJ#,WangJG#*,ZhangJB,LeeYM,FengGX,LimTK,ShenH-M,LinQS*,LiuB*.(#equalcontribution).(2016)Mechanism-GuidedDesignandSynthesisofMitochondria-targetingArtemisininAnalogwithEnhancedAnticancerActivity.Angew.Chem.Int.Ed.,55,13770-13774.7.WangJG#*,XuCC#,LunZR*,MeshnickSR.(2017)Unpacking“ArtemisininResistance”.TrendsinPharmacologicalSciences,38,506-5118.WangJG#*,GaoLQ#,LeeYM#,KaleshKA,OngYS,LimJ,LeeJE,SunHY,LeeSS*,HuaZC*,LinQS*.(2016)Targetidentificationofnaturalandtraditionalmedicineswithquantitativechemicalproteomicsapproaches.Pharmacology&Theraputics,162,10-22.9.ZhangJB#,WangJG#,ZhouZH,ZhangCJ,EunPJ,WuS,SzeSK,LinQS,ShenHM.(2017)AcetylationofTFEBactivateslysosomalfunctioninresponsetohistonedeacetylaseinhibitorSAHAtreatment.Autophagy,10.1080/15548627.2018.1447290.10.WangJG#,ZhangJB#,LeeYM,KohPL,NgSK,BaoFC,HuaZC,LinQS*,ShenHM*.(2016).QuantitativeChemicalProteomicsProfilingofdenovoProteinsSynthesisduringStarvation-MediatedAutophagy,Autophagy,12,1931-1944.11.ZhangJB#,WangJG#,NgS,LinQS*,ShenHM*.(2014).DevelopmentofanovelmethodforquantificationofautophagicproteindegradationbyAHAlabeling.Autophagy,10,901-912.12.ChenX,LiW,XuCC,WangJ,ZhuB,HuangQ,ChenD,ShengJ,ZouY,LeeYM,TanRX,ShenP,WongYK,LinQ,WangJG*,HuaZC*.(2018).Comparativeprofilingofanalogtargets:acasestudyonresveratrolformousemelanomametastasissuppression.Theranostics,inpress.13.WangJG#,TanXF#,NguyenVS,YangP,ZhouJ,GaoMM,LiZJ,LimTK,HeYK,OngCS,LayYF,ZhangJB,ZhuGL,LaiSL,GhoshD,MokYK,ShenHM,LinQS.(2014).AQuantitativeChemicalProteomicsApproachtoProfiletheSpecificCellularTargetsofAndrographolide,aPromisingAnticancerAgentthatSuppressesTumorMetastasis.Molecular&CellularProteomics,13,876-886.14.WangJG*#,WongYK#,ZhangJB#,LeeYM,HuaZC*,ShenHM*,LinQS*.(2017).DrugTargetIdentificationusinganiTRAQ-BasedQuantitativeChemicalProteomicsApproach.MethodsEnzymol.,586,291-309.15.ZhangJB#,WangJG#,LeeYM,LimTK,LinQS,ShenHM.(2017).Proteomicprofilingofdenovoproteinsynthesisinstarvation-inducedautophagyusingbio-orthogonalnoncanonicalaminoacidtagging.MethodsEnzymol.,588,41-59.