项目来源

德国科学基金(DFG)

项目主持人

LenaKeller

项目受资助机构

未公开

项目编号

329128825

立项年度

2016

立项时间

未公开

项目级别

国家级

研究期限

未知 / 未知

受资助金额

未知

学科

Biochemistry;Pharmacy

学科代码

未公开

基金类别

ResearchFellowships

关键词

未公开

参与者

ProfessorWilliamH.Gerwick

参与机构

未公开

项目标书摘要：Naturalproductshaveindisputablyplayedamajorroleinthedevelopmentofsmallmoleculedrugtherapy.Nevertheless,asrichandproductiveasthisapproachhasbeen,genomeminingeffortsofmicroorganismshaverevealedthattheypossessuntappedwealthintermsofbiosyntheticcapacitytoproducestructurallydiversenaturalproducts.Asaresult,genomemininghasbeenheraldedasarenaissanceforthefieldofnaturalproductsdrugdiscovery;however,thispromisehasnotbeenrealizedandsofar,genomeminingapproacheshavefallenshortofexpectations.Whilethereareamultitudeofpotentialproblemsthathavecontributedtothislackofproductivity,acentraldrawbackhasbeentheirrationalityofthesearchprocess;thatis,inmostcasesitisnotpossibletodeduceanythingaboutthepharmacologicalpropertiesofamoleculebasedonthegenestructureofitsbiosyntheticpathway.Therefore,thisproposaloutlinesanotherapproach,basedoncomputationalmethods,bywhichtomakegenomeminingforusefulnaturalproductsamoretargetedandrationalenterprise.Genomesequencedatafrommarinecyanobacteria(blue-greenalgae)willbeemployedtopredictthetherapeuticpotentialofacompoundbeforeitisevenisolated.Marinecyanobacteriaareparticularlysuitableforthisstudysincetheyhavebeenshowntopossessanenormouspotentialtoproducestructurallydiversenaturalproductsthatexhibitabroadspectrumofpotentbiologicalactivities.Beingneglectedbynaturalproductscientistsuntilthe1980s,cyanobacteriaarenowrecognizedasapromisingyetunderexploredsourcefornovelnaturalproducts.Asafirststep,genomicsequencedatawillbematchedwithmetabolomicsdatatoidentifytheexpressedmetabolomeandtocollectallavailableinformationaboutthemetabolites.Thisinformationwillbeusedtopredicthypotheticstructuresthatwillbetestedinaninversevirtualscreeningeffortwithasetoftargetproteins.ThesetconsistsoftenvalidatedtargetproteinsintheparasiticagentofChagasdisease,adiseasewithadevastatingchroniccourse.CompoundswillbeprioritizedfortheisolationprocessbasedontheirpotentialbindingactivityandtheirstructureswillbeelucidatedusingdetailedNMRanalysis.Asetofenzymaticandwholecellassayswillberuntoverifythepredictedbioactivitydata.Asuccessfulimplementationofthisapproachwouldhighlyincreasethechancestodiscoverbioactivenaturalproductsandtofocusthelaboratoryworkonbioactivecompounds.WiththededicationtonewnaturalproductsthattargetChagas,thisworkmightalsocontributetothedevelopmentofdrugsthathelptopreventthechroniccourseofthedisease.Furthermore,thedevelopedapproachcouldbetransferredtoothernaturalproductproducersaswellasdifferenttargetstructuresandwouldthereforeprovidethebasisforfurtherstudies.

Application Abstract: Naturalproductshaveindisputablyplayedamajorroleinthedevelopmentofsmallmoleculedrugtherapy.Nevertheless,asrichandproductiveasthisapproachhasbeen,genomeminingeffortsofmicroorganismshaverevealedthattheypossessuntappedwealthintermsofbiosyntheticcapacitytoproducestructurallydiversenaturalproducts.Asaresult,genomemininghasbeenheraldedasarenaissanceforthefieldofnaturalproductsdrugdiscovery;however,thispromisehasnotbeenrealizedandsofar,genomeminingapproacheshavefallenshortofexpectations.Whilethereareamultitudeofpotentialproblemsthathavecontributedtothislackofproductivity,acentraldrawbackhasbeentheirrationalityofthesearchprocess;thatis,inmostcasesitisnotpossibletodeduceanythingaboutthepharmacologicalpropertiesofamoleculebasedonthegenestructureofitsbiosyntheticpathway.Therefore,thisproposaloutlinesanotherapproach,basedoncomputationalmethods,bywhichtomakegenomeminingforusefulnaturalproductsamoretargetedandrationalenterprise.Genomesequencedatafrommarinecyanobacteria(blue-greenalgae)willbeemployedtopredictthetherapeuticpotentialofacompoundbeforeitisevenisolated.Marinecyanobacteriaareparticularlysuitableforthisstudysincetheyhavebeenshowntopossessanenormouspotentialtoproducestructurallydiversenaturalproductsthatexhibitabroadspectrumofpotentbiologicalactivities.Beingneglectedbynaturalproductscientistsuntilthe1980s,cyanobacteriaarenowrecognizedasapromisingyetunderexploredsourcefornovelnaturalproducts.Asafirststep,genomicsequencedatawillbematchedwithmetabolomicsdatatoidentifytheexpressedmetabolomeandtocollectallavailableinformationaboutthemetabolites.Thisinformationwillbeusedtopredicthypotheticstructuresthatwillbetestedinaninversevirtualscreeningeffortwithasetoftargetproteins.ThesetconsistsoftenvalidatedtargetproteinsintheparasiticagentofChagasdisease,adiseasewithadevastatingchroniccourse.CompoundswillbeprioritizedfortheisolationprocessbasedontheirpotentialbindingactivityandtheirstructureswillbeelucidatedusingdetailedNMRanalysis.Asetofenzymaticandwholecellassayswillberuntoverifythepredictedbioactivitydata.Asuccessfulimplementationofthisapproachwouldhighlyincreasethechancestodiscoverbioactivenaturalproductsandtofocusthelaboratoryworkonbioactivecompounds.WiththededicationtonewnaturalproductsthattargetChagas,thisworkmightalsocontributetothedevelopmentofdrugsthathelptopreventthechroniccourseofthedisease.Furthermore,thedevelopedapproachcouldbetransferredtoothernaturalproductproducersaswellasdifferenttargetstructuresandwouldthereforeprovidethebasisforfurtherstudies.