Antiparasitic and Antibacterial Drug Discovery: From Molecular Targets to Drug Candidates

490 Pages·2009·6.04 MB·English

Antiparasitic and Antibacterial
Drug Discovery
Edited by
Paul M. Selzer
Book Series
Drug Discovery in Infectious Diseases
ForthcomingTopics:
(cid:1)Viruses
(cid:1)Helminths
(cid:1)Apicomplexa
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Antiparasitic and Antibacterial Drug Discovery
From Molecular Targets to Drug Candidates
Edited by
Paul M. Selzer
TheEditor AllbookspublishedbyWiley-VCHarecarefully
produced.Nevertheless,authors,editors,and
Prof.Dr.PaulM.Selzer publisherdonotwarranttheinformationcontained
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IntervetInnovationGmbH errors.Readersareadvisedtokeepinmindthat
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55270Schwabenheim otheritemsmayinadvertentlybeinaccurate.
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LightmicroscopicimageofthehelminthSchistosoma
mansoni–withamalehostingafemaleinthecanalis Bibliographicinformationpublishedby
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UniversityofCaliforniaSanFrancisco,USA. DieDeutscheNationalbibliothekliststhis
Scanningelectronmicroscopicimageofthegram- publicationintheDeutscheNationalbibliografie;
negativebacteriaMannheimiaheamolytica:courtesy detailed bibliographicdataareavailableonthe
ofProf.Dr.LotharH.Wieler,FreieUniversitätBerlin, Internetathttp://dnb.d-nb.de.
Dr.HeikeKaspar,andDr.ChristophSchaudinn,
RobertKochInstitutBerlin,Germany.Thechemical #2009WILEY-VCHVerlagGmbH&Co.KGaA,
structureistakenfromchapter19authoredby Weinheim
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ISBN:978-3-527-32327-2
VII
Contents
Foreword V
Preface XI
List of Contributors XIII
PartOne DrugDiscoveryApproaches 1
1 TargetIdentificationandMechanism-BasedScreeningforAnthelmintics:
ApplicationofVeterinaryAntiparasiticResearchProgramstoSearchfor
NewAntiparasiticDrugsforHumanIndications 3
(cid:2)
TimothyG.Geary ,DebraJ.Woods,TraceyWilliams,andSolomonNwaka
2 AnthelminticResistanceasaGuidetotheDiscoveryofNewDrugs? 17
(cid:2)
Georgv.Samson-Himmelstjerna ,RogerK.Prichard,and
AdrianJ.Wolstenholme
3 DrugDiscoveryforNeglectedDiseases:ViewofAPublic–Private
Partnership 33
(cid:2)
RobDon andEricChatelain
4 BioinformaticsandChemoinformatics:KeyTechnologiesinthe
DrugDiscoveryProcess 45
(cid:2)
AndreasKrasky,AndreasRohwer,RichardJ.Marhöfer,andPaulM.Selzer
5 TargetIdentificationandValidationinAntiparasiticDrugDiscovery 59
(cid:2)
ChristianWolfandNikolasGunkel
6 SelectiveDrugTargetsinParasites 75
(cid:2)
PeterKöhler andRichardJ.Marhöfer
AntiparasiticandAntibacterialDrugDiscovery:FromMolecularTargetstoDrugCandidates.
EditedbyPaulM.Selzer
Copyright(cid:1)2009WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:978-3-527-32327-2
VIII Contents
7 LessonsLearnedfromTarget-BasedLeadDiscovery 99
MichaelGassel,JörgCramer,ChristopherKern,SandraNoack,
(cid:2)
andWolfgangStreber
8 ApproachesTowardsAntiparasiticDrugCandidatesfor
VeterinaryUse 117
(cid:2)
ChristopheChassaing andHaraldSekljic
9 LearningtoRelateStructuralSpacetoPropertySpace 135
MichaelBerger,JörgCramer,MichaelHinz,ChristinaMertens,
(cid:2)
ChristianMiculka ,TrevorNewton,JörgSchröder,andHaraldSekljic
10 RecruitingtheHostDefenseMechanisms:RolesforVaccines
andChemotherapeutics 159
(cid:2)
TheoP.M.Schetters
PartTwo ProtozoanParasites 175
11 ProteasesofParasiticProtozoa–CurrentStatusandValidation 177
(cid:2)
MohammedSajid ,MichaelJ.Blackman,PatriciaDoyle,ChenHe,
KirkwoodM.Land,CherylLobo,ZacharyMackey,MomarNdao,
SharonL.Reed,BrianShiels,RyanSwenerton,andWilliamWeir
12 InSearchofTrypanocidalDrugs 211
(cid:2)
LeopoldFlohé
13 TrypanosomatidProteinKinasesAsPotentialDrugTargets 227
(cid:2)
MartinWiese,AndrewMorris,andKarenM.Grant
14 TargetingtheMalariaKinome:DiscoveringKinaseInhibitors
asNovelAntimalarialAgents 249
(cid:2)
DayadeviJirage,SusanM.Keenan,andNormanC.Waters
15 MalariaandAntimalarials–aFocusedView 277
(cid:2)
FrankSeeber
PartThree MulticellularParasites 299
16 ChemotherapeuticDevelopmentStrategiesforSchistosomiasis 301
(cid:2)
ConorR.Caffrey ,DavidL.Williams,MatthewH.Todd,DavidL.Nelson,
JenniferKeiser,andJürgUtzinger
Contents IX
17 SearchingNewAntiparasiticsinVirtualSpace 323
FrankOellien,KristinEngels,JörgCramer,RichardJ.Marhöfer,
(cid:2)
ChristopherKern,andPaulM.Selzer
18 Cyclooctadepsipeptides–anAnthelminticallyActiveClass
ofCompoundsExhibitingaNovelModeofAction 339
(cid:2)
AchimHarder ,KathrynBull,MarcusGuest,LindyHolden-Dye,
andRobertWalker
19 ChemicalOptimizationofAnthelminticCompounds–ACaseStudy 357
(cid:2)
ThorstenMeyer ,JörgSchröder,ManfredUphoff,SandraNoack,
AnjaR.Heckeroth,MichaelGassel,PetraRohrwild,andThomasIlg
PartFour Bacteria 373
20 Pathogenomics:IdentificationofNovelDrugTargetsandVaccine
CandidatesinBacteria 375
(cid:2)
KnutOhlsen ,MartinEckart,UlrichDobrindt,HeikeBruhn,
andJörgHacker
21 TuberculosisDrugDiscovery:Issues,GapsandtheWayForward 415
(cid:2)
VéroniqueDartois ,FranzJoelLeong,andThomasDick
22 DecreasingtheNumberofGapsintheDraftAssemblyoftheMannheimia
haemolyticaM7/2GenomeSequence 441
HonQ.Tran,MathiasBeig,VolkerSpehr,AndreasRohwer,
(cid:2)
GottfriedUnden,andPaulM.Selzer
23 TotalSynthesisandConfigurationalAssignmentofPasteurestinAandB,
aNaturalProductwithAntimicrobialActivityonPasteurellaceae 453
(cid:2)
MarionKögl,LotharBrecker,RalfWarrass,andJohannMulzer
Index 473
V
Foreword
Itisironicthatthreedecadesagoinfectiousdiseaseswereviewedasaproblemofthe
past.Malariaandtuberculosisweregoingtobeeradicated,effectivevaccineswere
available for major childhood infections, and an armamentarium of antibiotics
was available for common community and hospital-acquired infections. Young
physicians were advised not to enter infectious disease specialties because they
were becoming irrelevant. The AIDS epidemic was the first wakeup call that
infectious diseases would again become a major global health problem. Drug-
resistant malariaand tuberculosis are nowalmost ubiquitous and new and emer-
ginginfectiousdiseasesarealmostaweeklystapleofthepopularpress.Indeedthe
needfornewdrugsforinfectiousdiseaseshasneverbeengreater.Globalindustry
and global travel means that formerly exotic diseases can rapidly establish them-
selvesatanyportofentry.Effectivevaccinesagainstthemostprevalentinfectious
diseaseslikeAIDSandmalariahaveprovendifficulttodevelop.Multidrug-resistant
organismsareanissueinanyclinicalsetting.Thispublicationprovidesawindowon
new approaches to drug discovery and development targeting infectious diseases.
Fortunately,technologyandtraininginnewmethodologiesofdrugdiscoveryhave
expandedrapidlyinthepast10years.Thechallengeishowtoeffectivelyapplythis
technology to the thorny problems of global infections and to maintain a drug
development pipeline for infectious diseases in light of the immense cost now
associatedwithbringingnewdrugstomarket.
SanFrancisco,USA JamesH.McKerrow
November2008
AntiparasiticandAntibacterialDrugDiscovery:FromMolecularTargetstoDrugCandidates.
EditedbyPaulM.Selzer
Copyright(cid:1)2009WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:978-3-527-32327-2
XI
Preface
In the age of antibiotics, vaccines, and drugs, we might be lulled into a sense of
complacencyregardinginfectiousdiseasesandthatthereis‘‘acureforeverything’’.
Thissenseofsecurityismaintainedatourperil,however.Onehasonlytoconsider
thegrowingdevastationcausedbysuchbig-namediseasesasinfluenza,HIV-AIDS,
tuberculosis, and malaria to see that the struggle to treat and control infectious
diseasesistrulytitanicandindeedbecomingmoreperilouswiththeever-evolving
developmentandspreadofdrugresistancecompoundedbythegreaterfreedomand
speedofmovementofgoods,animals,andpeople.Asidefromtherecentlyperceived
securitythreattothehealthandbusinessstructuresofthedevelopedworldcausedby
theseandaplethoraofotherinfectiousdisease,billionslivingindevelopingcountries
mustendurethedailystruggleofdiseases.Incontrasttomosthumanhealth-related
pharmaceutical companies, academic institutions, veterinary science, and animal
healthcompaniesremainverymuchfocusedoninfectiousdiseases,includingthose
causedbybacteriaandparasites.AsillustratedinFigure1,theanimalhealthsector
remainsprofitable,andthankfullyso,ashistoryhasshownthattherapiesproducedin
this sector often prove invaluable for treatment of similar infectious diseases of
humans–theapplicationofanthelminticsbeingacaseinpoint.
Theimprovedunderstandingoftheresilienceofdisease-causingagentstotherapies,
theirexpandingdiseasemenaceintheeraof‘‘globalization,’’andthebalanceprovided
bytheopportunitiesforcross-sectorexchangeofideasandapplicationsspurredthe
preparationofthisbook.Also,thebookservestohighlighttheimportanceandvisibility
ofdrugdiscoveryeffortsforinfectiousdiseasesofbothanimalsandhumans.
Though it is not possible to address every aspect, disease, or approach within a
single volume,thisbooksets fortha series ofcase studies andreview articles that
focusonbacterialandparasiticdiseasesinordertoshowcasehowscientistsinthe
differentdisciplinesstrivetomovedrugdiscoveryforward.Thecontributingauthors
areexpertsdrawnfromdrugdiscoveryunitsofthepharmaceuticalindustry,acade-
mia,andnonprofitorganizationsinanefforttoofferaglobalandbalancedinsight
intotheissuesandproblemsatstakeandtheirpossiblesolutions.
Writingthishasbeenarewardingtaskforeverybodyinvolved.Myheartfeltthanks
gotothecontributingauthorsfortheirexcellentworkperformedwithinashorttime-
frame. In addition, I am grateful to Intervet/Schering-Plough Animal Health and
its Drug Discovery Unit for their unreserved support, inspiration, and motivation
AntiparasiticandAntibacterialDrugDiscovery:FromMolecularTargetstoDrugCandidates.
EditedbyPaulM.Selzer
Copyright(cid:1)2009WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:978-3-527-32327-2
XII Preface
Figure1 Theworldanimalhealthmarketbased world),salesperanimalspecies,andsalesper
ondatafrom2006.Thefirstrowdepictsthe chemicalclass.Theareaoftheindividualpie
proportionofantiparasiticsandantiinfectivesin chartsisnotsize-adjusted.Originaldatawere
thewholeanimalhealthmarket.Rowstwoand derivedbyWoodMackenzieandkindlyprovided
threerepresenttheantiparasiticsand byLindaFranken-Horspool,International
antiinfectivesmarket,respectively.Fromleftto Marketing,Intervet/Schering-PloughAnimal
righttheindividualproportionsarebrokendown Health.
accordingtoregionalsales(ROW=restof
during the preparation of this book. I also thank the members of Intervet’s Bio-
ChemInformaticsUnitfortheirexcellenttechnicalbackingandteamspirit.Finally,I
amverygratefultoMsSimoneMaus-Gilbertforheroutstandingeditorialassistance.
Schwabenheim,Germany PaulM.Selzer
November2008