生物催化与新药研究和开发

:200783e2mail:[e-mail]3(210009),,,:Q503;O643132:A:10052281X(2007)1221947208BiocatalysisinDrugDiscoveryandDevelopmentChenYijun3WuXuri(LaboratoryofChemicalBiology,SchoolofLifeScienceandTechnology,ChinaPharmaceuticalUniversity,Nanjing210009,China)AbstractDuetotheadvantagesincludingmildconditions,highcatalyticefficiency,highstereoselectivityandregioselectivityandlessbyproducts,biocatalysishasbeenwidelyutilizedandappliedindrugdiscoveryanddevelopment.Moreover,biocatalystscanbestructurallychangedandoptimizedthroughnewtechnologiessuchasdirectedevolution,whichcouldbebettersuitedforbiocatalyticprocesses.Inthisreview,recentprogressinthefieldofapplicationofbiocatalysisindrugdiscoveryanddevelopmentisbrieflyintroducedanddiscussed.Keywordsbiocatalysis;biocatalyst;metabolites;chiraldrugs;drugdiscoveryanddevelopment70,,[1],,,,1,,,111,[2],(44%)(30%),[3],,,,pH[4],,112,,1912200712PROGRESSINCHEMISTRYVol.19No.12Dec.,2007,,,:(1);(2);(3);(4)[5]2,,3211,,,Michels[6],,,,,96,1625(bergenin1),(1):1bergenin[6]Fig.1Processofgeneratingbergeninderivativesbycombinatorialbiocatalysis[6]849119()()([7])()(),,,delaGÉutte[8],,212,P450,,,,[9]:(1);(2);(3);(4);(5);(6):(desloratadine7)(loratadine6)(2),10[10],,(cetirizine9)(hydroxyzine8)(2),H1[11],,[1215]213,2Loratadinehydroxyzine[10]Fig.2Biotransformationandactivemetabolitesofloratadineandhydroxyzine[10]P450,,(14)(S)262(11),62(10)1113,Streptomycesantibioticus(14)(S)262(11)[16](3)362Hydroxybuspironebuspirone[16]Fig.3Biotransformationof62hydroxybuspironeandbuspirone[16]9491123,,311,,,,,31111,44%,[3],[17]Goswami[18]AspergillusnigerRhodotorulaglutinis12{2,32dihydrobenzo[b]furan242yl}21,22oxirane(15)(S)2(16)(R)2(17),ee95%,45%(4),(S)2(S)232acetylthio222methylpropanoicacid(19)Patel[19]32acetylthio222methylpropanoicacid(18),19,24%,ee95%(4)31112,,,,2,,Campos[20]Pseudomonascepacia(21)R2(22)4[19]Fig.4Reactionscatalyzedbyhydrolyticenzymes[19](S)2(23)(5),(R)2(22)(R,R)2,,Patel[19]PS23032222(24),S2(25)R2(+)2(26)(5),2537%,ee97%,,5[19]Fig.5Esterificationreactionsinbiocatalysis[19]312,,31211,,059119,,,Ceranopril,2L2(29)Hanson[21]ProvidenciaalcalifaciensN222L2(27)28,28L22L2(29)(6),95%,ee9815%NADH(S)262(32)62(30)D222262(31)(S)262(32),3132(6),ee98%,R[22]NADH6[21,22]Fig.6Reactionscatalyzedbyoxidoreductases[21,22]31212,,35Patel[23]SphingomonaspaucimobilisL222(LAT)3435(7),LATE.coli2,(GOX),65%67%31213H+,H+,HIV21,(S)2tertiaryleucine(37)Thermoactinomycesintermedius3637(8),95%,ee9915%NADH[24](S)2allysineethyleneacetal(39)3,8,(S)2allysineethyleneacetal[25]Hanson[26]Thermoactinomycesintermedius38,39(8)NADH,CO2,1591127[23]Fig.7Reactionscatalyzedbyaminotransferases[23]8[24,26]Fig.8Reductiveaminationsinbiocatalysis[24,26]4,,,,pH,,,411,,,,[27]Declerck[28](),Pichiastipitis(PsXDH)Annaluru[29]PsXDH,,1018,2018,,[30,31],[32],,,,(R)2Terao[33]74(68277)188,,412,259119,,,(),,,[34],PCRDNAPCR,,PCR,4dNTPMg2+Mn2+TaqPCRDNADNA,;,,[35]PCRStephens[36]PCRThermomyceslanuginosus221,42,80,10min,90%,80,60min71%,70,215minDNADNase,,PCR,,PCR[37]DNADNA,DNADNA,,,,Fortin[38]PCRDNA(DoxG),DoxGDoxGsMA2,770DNA,familyshuflingRosic[39]DNAfamilyshufflingP450,P4505,,pH,,,,[1]RozzellDJ.Bioorg.Med.Chem.,1999,7(10):22532261[2]WandreyC,LieseA,KihumbuD.Org.ProcessRes.Dev.,2000,4(4):286290[3]StraathofAJ,PankeA,SchmidA.Curr.Opin.Biotech.,2002,13:548556[4]JohannesT,SimurdiakMR,ZhaoH.EncyclopediaofChemicalProcessing,2006,10:101110[5]FaberK.BiotransformationinOrganicChemistry,4thed.Germany:Springer2Verlag,1999.89[6]MichelsPC,KhmelnitskyYL,DordickJS,etal.TrendsBiotechnol.,1998,16(5):210215[7]MozhaevVV,BuddeCL,RichJO,eta1.Tetrahedron,1998,54(16):39713982[8]DelaGÉutteJT,KhanAJ,VulfsonEN.Biotechnol.Bioeng.,2001,75(1):9399[9]FuraA,ShuYZ,ZhuM,etal.J.Med.Chem.,2004,47(18):43404351[10]NormanP,DihlmannA,RabassedaX.DrugsToday,2001,37(4):215227[11]BenedettiMS,PlisnierM,KaiseJ,etal.Eur.J.Pharmacol.,2001,57(8):571582[12]ClissoldSP.Drugs,1986,32(suppl.4):4659[13]GilmanAG,GoodmanLS,RallTW,etal.ThePharmacologicalBasisofTherapeutics,7thed.NY:Macmillan,1985.674715[14]GilmanAG,GoodmanLS,RallTW,etal.ThePharmacologicalBasisofTherapeutics,7thed.NY:Macmillan,1990.383435[15]MeevesSG,AppajosyulaS.J.AllergyClin.Immunol.,2003,112(suppl.4):6977[16]HansonRL,ParkerWL,BrzozowskiDB,etal.Tetrahedron:Asymmetry,2005,16(16):27112716[17]SteinreiberA,FaberK.Curr.Opin.Biotech.,2001,12(6):552558[18]GoswamiA,TotlebenMJ,SinghAK,etal.Tetrahedron:Asymmetry,1999,10(16):31673175[19]PatelRN,HowellJM,McNameeCG,etal.Biotechnol.Appl.Biochem.,1992,16(1):3447[20]CamposF,BoschMP,GuerreroA.Tetrahedron:Asymmetry,2000,11(13):27052717[21]HansonRL,BembenekKS,PatelRN,etal.Appl.Microbiol.Biotechnol.,1992,37(5):599603359112[22]HansonR,SchwindenMD,BanerjeeA,etal.Bioorg.Med.Chem.,1999,7(10):22472252[23]PatelRN,BanerjeeA,NanduriV,etal.EnzymeMicrob.Technol.,2000,27(6):376389[24]PatelRN.EnzymeMicrob.Technol.,2002,31(6):804826[25]PatelRN.Biomol.Eng.,2001,17(6):167182[26]HansonR,HowellJ,LaPorteT,etal.EnzymeMicrob.Technol.,2000,26(5P6):348358[27]BornscheuerUT,PohlM.Curr.Opin.Chem.Biol.,2001,5(2):137143[28]DeclerckN,MachiusM,Wiegand