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I-Biotechnology•重组人粒细胞集落刺激因子•透明质酸•立妥昔单抗•干扰素•白细胞介素-2•疫苗我国生物技术药物•“现代生物制药”是高新技术产业，将成为“知识经济”的支柱产业之一•我国的现代生物制药行业仍然处于“技术初创期”–需要大量的资金投入–更需要“技术创新成果”的投入生物技术药物•传统生物技术制药（MedicalBiologicalProducts）–用生物发酵方法产生药物，如抗生素、维生素、氨基酸、药酒等–直接从动物及动物毒素制作的免疫制剂，如疫苗等–中药加工工艺加工成的药材（俗称“生药”和中成药等•生化制药（BiologicalDrugs）–从生物（多指动物）的组织或分泌物，中提取有效药用成份，如氨基酸、肽类、核酸类、酶类等•现代生物制药（Biopharmaceuticals）–以基因工程技术为基础的的生物制备技术，主要包括：•基因重组多肽、蛋白质类•基因药物，如基因疫苗和反义药物等•干细胞制剂WhatisBiotechnology•Theuseofcells(suchastissuesormicroorganisms)orbiologicalsubstances(suchasenzymes)toperformspecificindustrialormanufacturingprocesses.•Applicationsincludetheproductionofcertaindrugs,synthetichormones,andbulkfoodstuffsaswellasthebioconversionoforganicwaste.SyntheticBiology•Syntheticbiologyinarationalway:–reducebiologicalsystemstotheircomponentparts–buildnovelsystemsorrebuildexistingones–convergenceofbiology,engineeringandthephysicalsciences.•Syntheticbiologycanprovidenewprocessesforproducingchemicalsanddrugs–Artemisinin:anaturallyoccurring,anti-malarialdrug•Currentlyextractedfromaplantathighcostandwithlowefficiency•Ayeastcellsystemtransformedwithanewenzymepathwaycanproduceaprecursortotheactivedrug•Implications:–Creatingnewfunctionsfromnewcombinationsofcomponentparts–Improvingtheunderstandingofexistingbiologicalsystemsthroughreverseengineering.–Couldresultinthethirdindustrialrevolutionoverthenext50yearsKey#1ofBiotechnology:biotransformation•Theuseofenzymes–employedeitherasisolatedenzymes,crudeproteinextractsorwholecells–forthetransformationofnon-naturalorganiccompounds•Thetrendofapplyingnaturalcatalyststotransformnon-naturalorganiccompoundswasenhancedbytherecommendationoftheFDA-guidelines(1992)withrespecttotheuseofchiralbioactiveagentsinenantiopureform.生物技术药物的过程原料和前体生物反应器分离纯化产品保存基因工程菌株生物酶原始菌株动植物组织蛋白质无细胞表达系统Key#2:GeneTech.•RecombinantDNAtechnology–In1973:thefirstgenetransferintoEscherichiacoli.•Byusingmolecularbiologicalmethods,specificgeneistransferredinmicrobes,animalandplantcellsinorderto:–Improvementofyieldandproductivity–Productionofnovelcompounds–Extensionofsubstraterange–Developmentofnovelbiosyntheticroutesthatmayreplacechemicalsynthesisroutes–ImprovementofcellularpropertiesMetabolicengineering•Theimprovementofcellularactivitiesbymanipulating:–Enzymaticactivity–Transportproperties–RegulatoryfunctionsKey#3:IndustrialBioreactors•Inlaboratory:–Smallreactors,spinnerorshakeflasks•Industrialbioreactors–Largesize–Higherheterogeneityofthecultivationmedium–Exacerbatedturbulenceintensityandlocalshearforces•Causesstresstothemicro-organismsandcells.Key#4:Lyophilization•Moreorlessconsideredalaboratorycuriosityuntiltheendofthe1930s•SirErnstBorisChain,NobelLaureate,appliedfreeze-dryingforthefirsttimeforthepreservationofpenicillin•Aroutinetechnologyforthepreparationof:–Vaccines–Bloodplasmaandplasmafractions–Otherthermo-labileproducts冷冻干燥技术LyophilizersetupSamplechamberSamplesShelfCondenserVacuumpump基因重组技术代谢改造技术工业发酵技术（略）细胞/酶固定化技术MethodsofcellimmobilizationMatrix/supportcellgelimmobilizedgelcross-linkingreagentMethodsofenzymeimmobilization：microboxmicroboxenzymeMethodsofenzymeimmobilization:covalentlinkingMatrix/beadenzyme酶法合成介绍Enzymeforbiotransformation•Therearemanyenzymeswhichareverystrictlyboundtotheirnaturalsubstrate(s).Theyplayanimportantroleinmetabolismandtheyaregenerallynotapplicableforbiotransformations.•Ontheotherhand,animpressivenumberofbiocatalystshavebeenshowntopossessawidesubstratetolerancebykeepingtheirexquisitecatalyticpropertieswithrespecttochemoregionand,mostimportant,enantio-selectivity.PreparationofL-homocysteine±homocysteineAdenosineSAHhydrolaseAdenosyl-L-homocysteineAdenosineS-homocysteineL-homocysteine+InosineSAHhydrolaseAdenosinedeaminaseAdenosyl-L-homocysteineHPLCInosineL-homocysteineHPLCExamplesofbiosynthesis•手性氨基酸的酶合成方法2例思考题•什么是生物技术和生物技术药物•生物技术的核心和关键技术是什么？•什么是合成生物学？未来的影响有哪些？•青蒿素的前体药物的生物制备过程如何？•基于细胞的生物制备的基本流程如何？•基于生物酶的生物制备的基本流程如何？•什么是代谢工程改造？•基因工程在生物技术中的作用有哪些？•工业生物反应器和实验室生物反应器的异同有哪些？•什么是冷冻干燥?为什么冷冻干燥技术是生物技术产品制备的基本关键技术？•冷冻干燥的原理和技术要点是什么？•什么是固定化酶？其优缺点是什么？•为什么需要酶固定化，有那些方法？•生物制备对酶特性的要求有那些？•举一个酶法生物制备的例子？