糖類藥物進(jìn)展課件

Welcometo化學(xué)生物學(xué)!AdvancesinCarbohydrateDrugsandCarbohydrateVaccines糖類藥物與疫苗的研究進(jìn)展根據(jù)葉新山教授講義修改Partone糖類藥物的研究進(jìn)展Carbohydrate-baseddrugs,Carbohydratedrugs:糖類

或類似物構(gòu)成；Carbohydrate-modifieddrugs:糖修飾藥物（蛋白、

多肽、生物堿、抗生素）；iii.Carbohydratesusedindrugtargetinganddelivery

用于藥物尋靶和藥物轉(zhuǎn)運(yùn)的糖類化合物.含糖結(jié)構(gòu)的糖類藥物i.基于糖類的藥物(Carbohydrate-baseddrugs)肝素抗凝藥物、多糖疫苗、氨基糖苷抗生素、糖尿病藥物等ii.糖修飾的藥物(Carbohydrate-modifiedDrugs)糖基化現(xiàn)象是十分普遍現(xiàn)象；糖基的作用：增加溶解性、調(diào)節(jié)血漿半衰期、提高結(jié)合特異性；改變母體藥物的藥理活性糖修飾藥物的一些例子

蛋白、多肽的糖基化修飾；重組糖蛋白酶催化修飾技術(shù)，蛋白質(zhì)藥物iii.具有藥物轉(zhuǎn)運(yùn)作用的糖類化合物(Carbohydratesasdrugdeliveryagents)藥物尋靶(Drugtargeting)藥物轉(zhuǎn)運(yùn)(Drugdelivery)多糖：生物兼容性、物理性質(zhì)黏合劑、填充劑；微囊包裹，緩釋環(huán)糊精的特點(diǎn)及藥物轉(zhuǎn)運(yùn)細(xì)胞表面受體(Cell-surfacereceptors)細(xì)胞表面糖蛋白糖鏈細(xì)胞與細(xì)胞，細(xì)胞與胞外間質(zhì)，小分子與細(xì)胞糖鏈與糖鏈、與蛋白相互作用炎癥反應(yīng)－抗炎藥物腫瘤轉(zhuǎn)移和預(yù)后的標(biāo)志信號(hào)轉(zhuǎn)導(dǎo)，信號(hào)通道，基因表達(dá)的改變凝集素葡萄糖轉(zhuǎn)運(yùn)蛋白離子通道糖蛋白的重新攝取有關(guān)細(xì)胞內(nèi)受體(Intracellularreceptors)細(xì)胞外間質(zhì)(Extracellarmatrix)糖加工酶，控制細(xì)胞內(nèi)的代謝反應(yīng)糖基轉(zhuǎn)移酶溶酶體水解酶糖類化合物調(diào)控腫瘤、病毒感染、基因缺陷癥RNA,DNA靶點(diǎn)氨基糖苷類抗生素、烯二炔類抗生素高分子量多糖：透明質(zhì)酸、硫酸軟骨素、硫酸角質(zhì)素、硫酸皮膚素慢性疾病：骨關(guān)節(jié)炎，視網(wǎng)膜黃斑變性細(xì)胞外間質(zhì)多糖的降解：腫瘤轉(zhuǎn)移的信號(hào)酶抑制劑2、依據(jù)組成分類：簡(jiǎn)單糖類藥物：相對(duì)復(fù)合糖類而言，不含有糖類以外的其它成分；不同來源的多糖、寡糖和糖苷簡(jiǎn)單糖類藥物糖苷類藥物：中藥、植物藥有效成分－強(qiáng)心苷、皂苷、黃酮苷、氰苷等氨基糖苷類抗生素等人參皂苷的結(jié)構(gòu)糖苷類藥物糖苷類藥物部分糖苷類藥物的有效成分為苷元(配糖體)；而大部分的糖苷類藥物的生物效應(yīng)是糖基和苷元協(xié)同作用的結(jié)果。蛋白聚糖類藥物：肝素類藥物(HeparinandHeparanSulfate)Heparin重復(fù)序列Heparansulfate重復(fù)序列擬糖復(fù)合物藥物(neoglycoconjugates)：以糖鏈或含糖片斷修飾蛋白、糖脂、蛋白聚糖等大分子，形成新結(jié)構(gòu)、新功能的擬糖復(fù)合物。擬糖脂擬蛋白聚糖Glycodanderimer糖高聚物(glycopolymers)Glycomics糖組學(xué)(I)---CarbohydrateMicroarry糖類化合物的固載化方法Glycomics糖組學(xué)(I)---CarbohydrateMicroarry糖類藥物的模擬糖類化合物合成的難度極大！隨機(jī)肽庫DNA,RNA庫篩選糖類模擬物小分子化合物庫SialylLex

的模擬物1和2與E-selectin的親和力比sLex分別高10和20倍.開發(fā)海洋糖類藥物資源藻類資源：海藻膠，卡拉膠酸性多糖－凝集素配體－抗炎藥物－抗腫瘤活性－抗病毒，抗HIV活性2、改造已有的藥物多價(jià)糖綴合物的設(shè)計(jì)、合成“成簇效應(yīng)”Cluster,Dendrimer糖類化合物與受體(糖、蛋白、脂類)的結(jié)合力一般較弱，結(jié)合常數(shù)也較小，因此，很多情況下，糖表現(xiàn)為通過多位點(diǎn)的共價(jià)作用而實(shí)現(xiàn)一個(gè)強(qiáng)的相互作用－－多價(jià)糖綴合物使用糖類化合物的導(dǎo)向和定位作用糖類(半乳糖，甘露糖等)糖類激素(促甲狀腺素，促黃體酮激素等)微生物(幽門螺旋桿菌)微生物、植物毒素特定結(jié)構(gòu)糖類或特異性凝集素靶向或定位輸送作為新藥及基因轉(zhuǎn)運(yùn)劑的糖基膽酸酯及酰胺類化合物，它們的脂水兩親性使其能降低細(xì)胞膜的穩(wěn)定性而發(fā)揮定向轉(zhuǎn)運(yùn)作用

半乳糖－半乳糖結(jié)合蛋白(肝實(shí)質(zhì)細(xì)胞)肝趨向性使用糖類修飾，改變藥物的ADME,延長(zhǎng)半衰期蛋白質(zhì)藥物－酶切位點(diǎn)引入糖鏈－延長(zhǎng)半衰期胰島素－葡萄糖修飾－與CoA形成復(fù)合物－顆粒－緩釋3、開發(fā)新型的糖類農(nóng)藥糖類化合物作用于植物細(xì)胞－－綠色的糖類農(nóng)藥例如：寡糖素，植保素－－植物激素的生物效應(yīng)含長(zhǎng)鏈不飽和脂肪酸的甲殼寡聚糖植物根毛的彎曲根瘤合成、分泌的外多糖影響結(jié)瘤和成瘤后的固氮能力固氮菌與植物共生結(jié)瘤過程4、基于結(jié)構(gòu)或作用靶點(diǎn)的糖類藥物設(shè)計(jì)由于糖類藥物作用位點(diǎn)大多還不清楚，因此糖類藥物的研發(fā)中，這種有針對(duì)性的設(shè)計(jì)尚不多見。例1.針對(duì)糖苷(水解)酶過渡態(tài)設(shè)計(jì)的糖苷酶抑制劑例2.基于唾液酸的抗流感病毒的藥物設(shè)計(jì)神經(jīng)氨酸酶：斷裂唾液酸單元，使病毒釋放模擬酶底物唾液酸的構(gòu)象面臨的難題：復(fù)雜寡糖、糖綴合物的制備，連續(xù)、快速、低成本；糖類化合物血清清除速度快、口服給藥生物利用度差；藥理、毒理、藥物代謝評(píng)價(jià)模型，安全性、有效性.五、糖類藥物研究的關(guān)鍵技術(shù)和存在難題糖類化合物的分離、純化技術(shù)；糖類化合物結(jié)構(gòu)分析技術(shù)；糖類化合物的化學(xué)、生物合成水平的提高；糖類化合物生物學(xué)研究、藥理學(xué)評(píng)價(jià)方法的完善和提高.關(guān)鍵技術(shù)六、目前處于不同研究階段的糖類藥物1、已上市的糖類藥物(Carbohydrate-beseddrugstomarket)2、處于臨床研究的糖類藥物(Carbohydrate-basedTherapeuticsinDevelopment)3、處于臨床前研究的糖類藥物(AgentsinResearch)GenerialName(BrandName)IndicationComponyApprovalCountryandYearAcarbose(Precose,Glucobay,Prandase)DiabetesBayerAGU.S.in1995Voglibose(Basen,Glustat,AO-128)DiabetesTakedaandAbbottJapanin1994Miglitol(Glyset,Baym1099)DiabetesBayerU.S.in1996Dolsamate(Flavalfate,F3616M)GastriculcerationFaesSpainin2000Topiramate(Topamax)Anti-convulsantAnti-epilepticOrtho-McNeil,Johson&JohnsonU.S.in1996,1999Arbekacin(Habekacin)Anti-microbialMeijiSeikaJapanin1997Zanamivir(Relenza,GG167)Anti-ViralGlaxoSmithKlinesU.S.in1999Oseltamivir(Tamiflu)Anti-ViralHoffmann-LaRoche,GileadU.S.in1999已上市的糖類藥物(Carbohydrate-beseddrugstomarket)GenerialName(BrandName)IndicationComponyApprovalCountryandYearPneumococcal(HeptavalentVaccine,Prevnar)ConjugatevaccineWyethU.S.in2000Haemophilusb(ActHIB,OmniHIB)ConjugatevaccineSmithKlineBeecham,PasteurMerieuxFrancein1996TyphoidVi(TyphimVi)ConjugatevaccinePasteurMerieuxU.S.in1995Drotrecoginalfa(Xigris)SepsisLillyU.S.in2001Dalteparin(Fragmin)Anti-coagulant,antithromboticPharmaciaUpjohnU.S.in2000Enoxaparine(Lovenox)Anti-coagulant,antithromboticAventisU.S.in1998Nadroparine(Fraxiparine)Anti-coagulant,antithromboticSanofi-synthelaboFrancein1986Ardeparin(Normiflo)Anti-coagulant,antithromboticOrganonU.S.in2000(Continued)已上市的糖類藥物(Carbohydrate-beseddrugstomarket)GenerialName(BrandName)IndicationComponyApprovalCountryandYearDanaparoid(Orgaran)Anti-coagulant,antithromboticOrganonU.S.in2000Fondaparinux(Arixtra)Anti-coagulant,antithromboticOrganonandSanofi-synthelaboU.S.in2001Hyaluronicacid(Orthovisc)ViscoelasticSupplementAnlka,ZimmerEuropeEuropeandCanadain1998Imiglucerase(Cerezyme)Gaucher’sdiseaseGenzymerU.S.in1994Agalsidasealfa(Replaga)Fabry’sdiseaseTranskaryoticTherapiesEuropein2001(Continued)已上市的糖類藥物(Carbohydrate-beseddrugstomarket)Name

Generic(Code)IndicationComponyDevelopmentMitemcinal(GM-11)Gastroparesis;gastroesophagealreflexChugaiPhaseIIEM-574Chronicgastritis;gastroesophogealreflexTakeda,KitazatoPhaseIISygen(GM-1)Parkinson’sdisease,spinalcordinjuryFidiaPhaseIIEverninomicin(Ziracin,SCH27899)AntibioticSchering-PloughDiscontinued(PhaseII)NE-1530PediatricearinfectionNeoseDiscontinued(PhaseII)NE-0080HelicobacterpyloriinfectionNeoseDiscontinued(PhaseI)SynsorbPkE.ColiO157:H7HemolyticuremicsyndromeSynsorbDiscontinued(PhaseIII)處于臨床研究的糖類藥物(Carbohydrate-basedTherapeuticsinDevelopment)Name

Generic(Code)IndicationComponyDevelopmentSynsorbCdC.DifficileassociateddiarrheaSynsorbDiscontinued(PhaseIII)Peramivir(RWJ-270201)Anti-viralJohnson&JohnsonBiocrystPhaseIIISC48334(N-Butyl-deoxynojirimycin)HIV/ARCSearleDiscontinued(PhaseII)Celgosivir(MDL-28574,DRG-0202)HIVAventisDiscontinued(PhaseII)E.ColiO157VaccineE.ColiO157infectionNICHHDPhaseIHeparinaseI(Neutralase)Anti-coagulationreversalBioMarinPhaseIIDeligoparin(OP2000)Antithrombosis,InflammatoryboweldiseaseOpocrin,Incara,ElanPhaseIII(Continued)處于臨床研究的糖類藥物(Carbohydrate-basedTherapeuticsinDevelopment)Name

Generic(Code)IndicationComponyDevelopmentCylexinReperfusioninjuryCytelDiscontinued(PhaseII)rPSGL-Ig,PSGL-1HeartattackWyethDiscontinued(PhaseII)Theratope(SialylTnAgconjugatevaccine)Metastaticcolorectal,breastcancerBiomiraPhaseIIIGloboHconjugatevaccineBreast,postatecancerMemorialSloan-KetteringcancerCenterPhaseIGMK(GM2KLH/QS-21conjugatevaccineMalignantmelanomaProgenics,Bristol-MyersSquibbDiscontinued(PhaseIII)MGV(GM2/GD2KLHQS-21conjugatevaccineColorectal,gastric,small-celllung,cancerProgenics,Bristol-MyersSquibbDiscontinued(PhaseII)PI-88Multiplemyeloma,TumorangiogenesisProgen,MedigenPhaseII(Continued)處于臨床研究的糖類藥物(Carbohydrate-basedTherapeuticsinDevelopment)Name

Generic(Code)IndicationComponyDevelopmentGCS100(GBC-590)PancreaticcanceradenocarcinomaSafeSciencePhaseIIGD0039(Swainsonine)Renal,colorectal,breastcancerGlycoDesignPhaseIIVevesca15(OGT918,N-butyldeoxy-nojirimycin)Fabry’s,Gaucher’sdiseaseOxford,GlycoSciencesPhaseIIIAlpha-L-iduronidase(Aldurazyme)MPSIBioMarin,GenzymePhaseIGMK(GM2KLH/QS-21conjugatevaccineMalignantmelanomaProgenics,Bristol-MyersSquibbPhaseIIIArylsulfataseBMPSVIBioMarinPhaseII(Continued)處于臨床研究的糖類藥物(Carbohydrate-basedTherapeuticsinDevelopment)Name

Generic(Code)IndicationMechanismCompony/InstitutionDYN12DiabetesAmadorase/fructoseamine-3-kinaseinhibitionDynamisTherapeuticsVancomycinanalogesAnti-bacterialCellwallbiosynthesisinhibitionPrincetonUniversityOlivomycinAAnti-bacterialAnti-cancerDNAminogroovebindingUniversityofMichiganS.Aureusvaccine,(NSG,poly-N-succinyl--1-6glucosamine),Anti-bacterialVaccineHarvardMedicalSchoolNIAIDpolysialicacid,nppolySA,KLH,QS-21Meningitis,cancerVaccineMemorialSloan-KetteringCancerCenterN-nonyldeoxynojirimycin(NN-DNJ)Anti-viralInhibitionofglycoproteinfoldingIgXOxfordHepatitis處于臨床前研究的糖類藥物(AgentsinResearch)Name

Generic(Code)IndicationMechanismCompony/InstitutionTnMBR1LewisYKLHAnti-cancerMulti-antigenic,UnimolecularvaccineMemorialSloan-KetteringCancerCenterGalactopyranosyl--D-mannopyranosideAnti-inflammatoryLeukocytetrafficUCSanDiegoLewisyepitopeAnti-cancerLewisyclusteringvaccineMemorialSloan-KetteringCancerCenter-1,6-GlcNAc-branchedN-glycanAnti-cancerGlcNAc-TVmodulation,Mgat5geneUniversityofTorontoManLevAnti-cancerToxinsorimmunerecognitionGlycoDesignUCBerkeley(Continued)處于臨床前研究的糖類藥物(AgentsinResearch)4、目前處于不同研究階段的糖類藥物的適應(yīng)癥類型Diabetes糖尿病Acarbose,Voglibose,miglitol－－-glucosidase抑制劑Non-insulin-dependentdiabetes(Type2)GastrointestinalSystem胃腸道系統(tǒng)藥物Dosmalfate–gastric,duodenal,esophagealulcers胃，十二指腸，食道潰瘍Centralnervoussystem中樞神經(jīng)藥物糖類藥物可作用于CNS！－糖的脂水分配系數(shù)的可調(diào)節(jié)Topiramate—anti-convulsantandepilepsy抗驚厥和抗癲癇Infectin抗感染藥物Antibiotics—aminoglycosideantibioticsAntiviralDrugs—influenza/Sepsis(膿毒癥)/antiviralGlycoconjugateVaccine—肺炎、腦膜炎；細(xì)菌莢膜多糖HibVaccine:上市了4中此類疫苗Thrombosis抗血栓藥物－anticoagulant(AT,FactorXa)Heparin(1937’s)LMWHeparinDaltrparinEnoxaparinNadroparineArdeparinDanaparoidFondaparinux:合成的肝素五糖Inflammation抗炎藥物－細(xì)胞外間質(zhì)(Extracellarmatrix)Hyaluronicacid透明質(zhì)酸－Osteoarthritis骨關(guān)節(jié)炎EnzymeReplacement酶置換療法治療代謝疾病GeneticCause–Saccharide-processingenzyme--Saccharide/glycoconjugatemetabolitesGlycolipidstoragedisease溶酶體蓄積癥Carbohydrate-basedVaccines糖類疫苗Gaucher’sdisease—缺乏glucerbrosidaseFabry’sdisease—缺乏-galactosidaseA補(bǔ)充酶制劑：Imiglucerase(Gaucher’s)AgalsidaseAlfa(Fabry’s)PartTwoAdvancedinCarbohydrate-basedVaccine糖疫苗研究進(jìn)展由于糖基化是生命過程中普遍存在的現(xiàn)象，而承載重要生物學(xué)功能的糖綴合物之糖鏈在病理過程中的異常和高表達(dá)以及異種生物糖鏈的特殊性，使糖類化合物作為抗原決定簇而引起特異性免疫反應(yīng)，已為實(shí)驗(yàn)所證實(shí)。基于此的糖類疫苗研究在近幾年來取得了突破性的結(jié)果，已有針對(duì)新生兒、幼兒肺炎和腦膜炎的Hib疫苗上市，有針對(duì)瘧疾、腫瘤、艾滋病和多種真菌、細(xì)菌和原生物感染的糖類疫苗處于不同的研究階段，顯示出了誘人的前景。為什么糖類化合物可以作為疫苗分子？特異性的抗原決定簇的存在Immunodominantepitopes糖疫苗形成球狀的質(zhì)脂體epitopeslinkercarriesChemical&EngineeringNews,August9,

2004

Volume82,Number32,pp.31-35

糖類疫苗的研究已取得重要進(jìn)展，引起廣泛關(guān)注！糖類疫苗的研究已取得重要進(jìn)展，引起廣泛關(guān)注！腫瘤相關(guān)糖抗原TACA疾病相關(guān)糖抗原的存在是研制糖類疫苗的基礎(chǔ)在病理過程中，細(xì)胞表面的糖綴合物之糖鏈的異常和高表達(dá)以及異種生物糖鏈的特異性和高表達(dá)，使利用糖類化合物作為抗原決定簇而引起特異性免疫反應(yīng)，研制糖類疫苗成為可能.腫瘤細(xì)胞表面糖鏈的異常表達(dá)腫瘤細(xì)胞表面部分糖抗原結(jié)構(gòu)已鑒定結(jié)構(gòu)的血吸蟲糖抗原結(jié)構(gòu)(I)寄生蟲的糖鏈結(jié)構(gòu)與人體細(xì)胞表面糖鏈結(jié)構(gòu)存在很大的差異！已鑒定結(jié)構(gòu)的血吸蟲糖抗原結(jié)構(gòu)(II)糖類疫苗的研究進(jìn)展1、Capsularpolysaccharideproteinconjugate-basedvaccines/Bacterialcapsularpolysaccharidevaccines細(xì)菌莢膜多糖疫苗HaemophilusInfluenzaeTypeB(Hib)—polysaccharideHib+conjugatedtodifferentproteincarries致病原體的外殼：弱免疫原性的多糖，逃避宿主免疫監(jiān)控基于這種多糖結(jié)構(gòu)的疫苗：感染性疾病控制ApproachesKBacterialPolysaccharides(PS)BacterialPS-proteinconjugateSyntheticantigen-proteinconjugateBacterialPS-syntheticT-cellepitopesSpecifficproductnamePneumovaxMenomunaMenactraTMVaem-HibHiberixQuimi-HibTheratopePADREProsConsEasyaccessImmunityonlylast2-5years,potentialcontaminationbybacterialcomponentsImmunitylast10-15yearsComplexanalysis/purificationLargescaleaccess,easeofqualitycontrolHereogeneousintheproteincomplexSpecificimmuneresponseHerteogeneousinthecarbohydrateconplexGroupsandcompaniesusingitMerck&CoAventisPasteurAventisPasteurCh