Chemokine Receptors as Drug Targets (Methods and Principles in Medicinal Chemistry)

396 Pages·2010·4.035 MB·English

by  Martine J. Smit, Sergio A. Lira, Rob Leurs, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers

Edited by
MartineJ.Smit,SergioA.Lira,
and Rob Leurs
Chemokine Receptors
as Drug Targets
Methods and Principles in Medicinal Chemistry
Editedby R. Mannhold,H.Kubinyi, G.Folkers
EditorialBoard
H.Buschmann, H.Timmerman, H.van de Waterbeemd, T.Wieland
Previous Volumes of this Series:
Ghosh, Arun K.(Ed.) van deWaterbeemd, Han/Testa,
Aspartic Acid Proteases as Bernard(Eds.)
Drug Bioavailability
Therapeutic Targets
EstimationofSolubility,Permeability,
2010
AbsorptionandBioavailability
ISBN:978-3-527-31811-7
Second,CompletelyRevisedEdition
Vol.45
2008
Ecker, GerhardF. /Chiba,Peter (Eds.)
ISBN:978-3-527-32051-6
Transporters as Drug Carriers Vol.40
Structure,Function,Substrates
Ottow,Eckhard/Weinmann, Hilmar
2009 (Eds.)
ISBN:978-3-527-31661-8 Nuclear Receptors as Drug
Vol.44
Targets
Faller,Bernhard /Urban,Laszlo(Eds.)
2008
Hit and Lead Profiling
ISBN:978-3-527-31872-8
IdentificationandOptimizationof Vol.39
Drug-likeMolecules
Vaz,Roy J./Klabunde, Thomas(Eds.)
2009
Antitargets
ISBN:978-3-527-32331-9
PredictionandPreventionofDrugSide
Vol.43
Effects
Sippl, Wolfgang/Jung,Manfred (Eds.)
2008
Epigenetic Targets in Drug
ISBN:978-3-527-31821-6
Discovery Vol.38
2009 Mannhold,Raimund (Ed.)
ISBN:978-3-527-32355-5 Molecular Drug Properties
Vol.42
MeasurementandPrediction
Todeschini,Roberto/Consonni,Viviana 2007
Molecular Descriptors for ISBN:978-3-527-31755-4
Chemoinformatics Vol.37
VolumeI:AlphabeticalListing/Volume Wanner,Klaus/Höfner, Georg (Eds.)
II:Appendices,References Mass Spectrometry in
2009 Medicinal Chemistry
ISBN:978-3-527-31852-0
ApplicationsinDrugDiscovery
Vol.41
2007
ISBN:978-3-527-31456-0
Vol.36
Edited by
Martine J. Smit, Sergio A. Lira, and Rob Leurs
Chemokine Receptors as Drug Targets
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[email protected] #2011WILEY-VCHVerlag&Co.KGaA,
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Allrightsreserved(includingthoseoftranslationinto
Prof.Dr.MartineJ.Smit otherlanguages).Nopartofthisbookmaybe
VUUniversityAmsterdam reproducedinanyform–byphotoprinting,
FacultyofSciences microfilm,oranyothermeans–nortransmittedor
DepartmentofMedicinalChemistry translatedintoamachinelanguagewithoutwritten
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1081HVAmsterdam specificallymarkedassuch,arenottobeconsidered
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Printedonacid-freepaper
Prof.Dr.RobLeurs
VUUniversityAmsterdam ISBN:978-3-527-32118-6
FacultyofSciences
DepartmentofMedicinalChemistry
Leiden/AmsterdamCenterforDrugResearch
DeBoelelaan1083
1081HVAmsterdam
TheNetherlands
V
Contents
List of Contributors XV
Preface XXI
A Personal Foreword XXIII
PartOne FundamentalsofChemokinesandChemokineReceptors 1
1 StructuralAspectsofChemokinesandtheirInteractionswithReceptors
andGlycosaminoglycans 3
AmandaE.I.Proudfoot,IndiaSeverin,DamonHamel,
andTracyM.Handel
1.1 Introduction 3
1.2 Receptor–LigandInteractions 5
1.3 LigandStructure 8
1.3.1 TertiaryandQuaternaryStructures 8
1.3.2 FunctionalRoleofTertiaryandQuaternaryStructures 12
1.3.3 Hetero-Oligomerization 13
1.4 ReceptorStructure 13
1.4.1 ModificationstotheN-TerminiofChemokinesandtheir
EffectonReceptorActivation 16
1.5 GlycosaminoglycanBindingSites 17
1.6 ChemokineAnalogs–ResearchToolsandPotentialTherapeutics? 20
References 23
2 StructuralInsightsforHomologyModelingofChemokineReceptors 33
LeonardoPardo,XavierDeupi,ArnauCordomí,CedricGovaerts,
andMercedesCampillo
2.1 Introduction 33
2.2 Chemokines 35
2.3 TheTransmembraneDomainofChemokineReceptors 36
2.3.1 TransmembraneHelix1 37
2.3.2 TransmembraneHelix2 37
ChemokineReceptorsasDrugTargets.EditedbyMartineJ.Smit,SergioA.Lira,andRobLeurs
Copyright(cid:1)2011WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:978-3-527-32118-6
VI Contents
2.3.3 TransmembraneHelix3 38
2.3.4 TransmembraneHelix4 38
2.3.5 TransmembraneHelix5 39
2.3.6 TransmembraneHelix6 39
2.3.7 TransmembraneHelix7 39
2.4 StructuralandFunctionalRoleofInternalWaterMolecules 40
2.5 TheStructureoftheExtracellularDomainofChemokineReceptors 41
2.6 TheStructureoftheIntracellularDomain 41
2.7 TheBindingofChemokinestoChemokineReceptors 41
2.8 TheBindingofSmall-MoleculeLigandstoChemokineReceptors 42
2.9 MolecularProcessesofReceptorActivation 42
2.10 TheBindingoftheGProtein 44
2.11 ReceptorOligomerization 45
2.12 Conclusions 45
References 45
3 SignalingEventsInvolvedinChemokine-Directed
TLymphocyteMigration 51
StephenG.Ward
3.1 TheRoleofGTPasesinChemokine-DirectedLymphocyte
Migration 51
3.2 Class1PI3KsandtheirRoleinCellMigration:AnOverview 52
3.3 DoPI3K-DependentSignalsContributetoTLymphocyte
MigrationinResponsetoChemokines? 53
3.4 RoleofPI3KinTLymphocyteHomingandMigrationInVivo 54
3.5 RoleofPI3KinInterstitialTLymphocyteMotility 55
3.6 RoleofPhospholipaseCandProteinKinaseCSignaling
inChemokine-DirectedTLymphocyteMigration 56
3.7 ConcludingRemarksandFutureDirections 57
References 59
4 TheAtypicalChemokineReceptors 67
MarkD.Singh,RobertJ.B.Nibbs,andGerardJ.Graham
4.1 D6,anAtypicalReceptorforPro-InflammatoryCCChemokines 67
4.1.1 D6ScavengesChemokinesInVitro 68
4.1.2 D6ExpressionInVivo 69
4.1.3 ExplorationsofD6FunctionInVivo 70
4.2 CCX-CKR,anAtypicalReceptorforHomeostaticCCChemokines 73
4.3 CXCR7:ASecondReceptorforCXCL11andCXCL12withCritical
RolesinDevelopmentandTumorigenesis 75
4.3.1 CXCR7inDevelopment 75
4.3.2 CXCR7inCancer 76
4.4 DARC:APromiscuousPro-InflammatoryAtypicalChemokineReceptor
onRedBloodCellsandEndothelialCells 77
4.4.1 FunctionofChemokineBindingtoDARC 77
Contents VII
4.4.2 DARCInteractswithNon-ChemokineProteins 78
4.4.3 WhatCanDARCNegativePeopleTellUsAboutDARCFunction? 79
4.5 Summary 79
References 79
5 TargetingChemokineReceptorDimers:Arethere
Two(orMore)toTango? 85
HenryF.Vischer,SaskiaNijmeijer,andMarcParmentier
5.1 Introduction 85
5.2 ChemokinesandtheirReceptors 85
5.3 GPCRsExistandFunctionasDimers 86
5.4 DetectionofGPCRDimerization 87
5.5 ChemokineReceptorDimerization 90
5.6 ConstitutiveVersusInducedChemokineReceptorDimerization 93
5.7 FunctionalConsequencesofChemokineReceptorDimerization 95
5.8 (Patho-)PhysiologicalConsequencesofChemokineReceptor
Dimerization 95
5.8.1 ChemokineReceptorHeterodimerizationwithChemokine
Receptors 96
5.8.2 ChemokineReceptorHeterodimerizationwithDecoy
ChemokineReceptor 96
5.8.3 ChemokineReceptorHeterodimerizationwithVirally
EncodedGPCRs 96
5.8.4 ChemokineReceptorHeterodimerizationwithOpioidReceptors 97
5.8.5 ChemokineReceptorHeterodimers:InnovativeDrugTargets? 97
References 98
PartTwo ChemokineReceptorsinDisease 105
6 ChemokineReceptorsinInflammatoryDiseases 107
AlettaD.Kraneveld,SaskiaBraber,SaskiaOverbeek,PetradeKruijf,
PimKoelink,andMartineJ.Smit
6.1 Introduction 107
6.2 ChemokineReceptorsonInflammatory/ImmuneCells 108
6.2.1 ChemokineReceptorsandInnateImmuneCells 108
6.2.1.1 MonocytesandMacrophages 108
6.2.1.2 DendriticCells 109
6.2.1.3 Neutrophils 109
6.2.1.4 Eosinophils 110
6.2.1.5 Basophils 110
6.2.1.6 MastCells 111
6.2.1.7 NaturalKillerCells 111
6.2.2 ChemokineReceptorsandAdaptiveImmuneCells 112
6.2.2.1 BLymphocytes 112
6.2.2.2 TLymphocytes 113
VIII Contents
6.2.3 Conclusion 114
6.3 ChemokineReceptorsandInflammatoryLungDiseases 114
6.3.1 COPD 116
6.3.2 ChemokineReceptorsinCOPD 116
6.3.3 Asthma 118
6.3.4 ChemokineTargetsinAsthma 119
6.4 ChemokineandInflammatoryBowelDiseases 121
6.4.1 InflammatoryBowelDisease 121
6.4.2 ChemokineReceptorsinInflammatoryBowelDisease 122
6.4.3 Chemokine-MediatedNeuronalActivationinInflammatory
BowelDisease 124
6.5 ChemokineReceptorsandRheumatoidArthritis 125
6.5.1 RheumatoidArthritis 125
6.5.2 ChemokineReceptorsandTheirLigandsinRheumatoidArthritis 126
6.6 ChemokineReceptorsandAtherosclerosis 128
6.6.1 Atherosclerosis 128
6.6.2 ChemokineandtheirReceptorsinAtherosclerosis 129
6.7 ChemokineReceptorsinMultipleSclerosis 131
6.7.1 MultipleSclerosis 132
6.7.2 ChemokinesandtheirReceptorsinMultipleSclerosis 132
6.8 ChemokineReceptorsandPsoriasis 134
6.8.1 Psoriasis 134
6.8.2 ChemokinesandtheirReceptorsinPsoriasis 135
6.9 ConcludingRemarks 136
References 137
7 ChemokinesandtheirReceptorsinCentralNervous
SystemDisease 151
KnutBiberandHendrikusW.G.M.Boddeke
7.1 Introduction 151
7.2 FamiliesofChemokines 151
7.3 ChemokinePharmacology 152
7.4 ChemokinesandChemokineReceptors:AComplexSystem 152
7.4.1 ExpressionofChemokinesandtheirReceptorsintheCNS 153
7.4.2 InvolvementofChemokinesinBlood–BrainBarrierDisruption
AssociatedwithNeurodegenerativeDisease 153
7.5 TheRoleoftheChemokinergicSysteminMultipleSclerosis
andExperimentalAutoimmuneEncephalitis 154
7.5.1 Chemokines:AttractorsforBloodLymphocytesinMSandEAE? 154
7.6 TheRoleofChemokinesinBrainIschemia 155
7.6.1 FunctionalInvolvementofChemokinesinIschemic
Neurodegeneration 156
7.7 ChemokinesinHIV-AssociatedDementia 157
7.7.1 InvolvementofChemokineReceptorsinHIVInfection
oftheBrain 157
Contents IX
7.7.2 InvolvementofCXCR4ingp120-InducedNeurotoxicity 157
7.7.3 TheRoleofCX3CL1inHAD 158
7.8 ChemokinesinNeuropathicPain 159
7.9 Conclusions 160
References 160
8 ChemokinesandCancerMetastasis 167
AmandaBurkhardtandAlbertZlotnik
8.1 Introduction 167
8.2 CXCR4andCCR7ReceptorsPlaySpecialRolesinCancer
Metastasis 168
8.3 RetrospectiveClinicalDataSupportsaRoleforChemokines
inCancerMetastasis 169
8.4 HowDoestheCXCR4/CXCL12AxisInfluencetheDevelopment
ofMetastaticLesions? 170
8.5 CXCR4isaKeyPlayerintheDevelopmentofZebrafish;
RoleofCXCR7 170
8.6 TheCXCR4/CXCL12AxisinStemCellHomingintheBone
Marrow 172
8.7 ConclusionsandFutureDirections 172
References 173
9 ConstitutivelyActiveViralChemokineReceptors:ToolsforImmune
SubversionandPathogenesis 177
DavidMaussang,GeroldBongers,SergioA.Lira,andMartineJ.Smit
9.1 Introduction 177
9.2 HerpesvirusesandViralDiseases 180
9.2.1 TheBetaherpesviridaeSubfamily 180
9.2.1.1 TheCytomegalovirusGenus:HHV-5/HCMV 180
9.2.1.2 TheRhesolovirusGenus:HHV-6andHHV-7 183
9.2.2 TheGammaherpesviridaeSubfamily 183
9.2.2.1 TheLymphocryptovirusGenus:HHV-4/EBV 183
9.2.2.2 TheRhadinovirusGenus:HHV-8/KSHV 183
9.3 HerpesvirusesEncodeConstitutivelyActiveViralChemokine
Receptors 184
9.3.1 HumanCytomegalovirusEncodesFourDifferentViralG
Protein-CoupledReceptors 184
9.3.1.1 TheChemokineReceptorUS28MediatesHCMV-Induced
(Patho)PhysiologicalEffects 184
9.3.1.2 TheConstitutivelyActiveOrphanChemokineReceptor
UL33 188
9.3.1.3 TheChemokineReceptor-RelatedUS27andUL78Orphan
Receptors 188
9.3.2 Roseoloviruses-EncodedChemokineReceptors:TheU12and
U51Genes 189
X Contents
9.3.3 EBV-EncodedConstitutivelyActiveOrphanvGPCRBILF1 190
9.3.4 ORF74,theTumorigenicConstitutivelyActiveChemokineReceptor
EncodedbyKSHV 190
9.3.4.1 ORF74ConstitutivelyActivatesMultipleSignalingPathways
inDifferentCellTypes 191
9.3.4.2 ORF74ExpressionMimicsKSHV-InducedTransformation 193
9.4 ConcludingRemarks 194
References 196
PartThree TargetingChemokineReceptors 207
10 CCR5AntagonistsinHIV 209
DavidC.PrydeandChristopherG.Barber
10.1 Introduction 209
10.1.1 HIVandAIDS 209
10.1.2 ViralEntryasaTherapeuticTarget 210
10.1.3 CCR5asaTherapeuticTarget 211
10.1.4 EnablingDrugDiscoveryProgramsTargetingCCR5 211
10.2 CCR5AntagonistPrograms 212
10.2.1 Merck 212
10.2.2 Novartis 214
10.2.3 Pfizer 215
10.2.4 Incyte 218
10.2.5 ScheringPlough 218
10.2.6 Berlex 220
10.2.7 GlaxoSmithKline/Ono 220
10.2.8 Takeda 221
10.2.9 AstraZeneca 222
10.2.10 RecentDisclosures 222
10.2.11 OverviewofPublishedCCR5Antagonists 224
10.3 MolecularInteractionsandBindingModesofCCR5Receptor
Antagonists 225
10.4 ResistancetoCCR5ReceptorAntagonists 227
10.5 Outlook 228
References 229
11 CXCR4asaTherapeuticTarget 239
KenY.C.ChowandFrançoiseBachelerie
11.1 BiologyandPhysiologicalRoleofCXCR4 239
11.1.1 GeneralIntroduction 239
11.1.2 RegulationofCXCR4Expression 240
11.1.2.1 TranscriptionalRegulation 240
11.1.2.2 Post-TranscriptionalRegulation 241
11.1.3 PhysiologicalFunctionsoftheCXCR4Receptor 242
11.1.3.1 RoleinLeukocytesTraffickingandDevelopment 242