Protein Phosphorylation in Parasites: Novel Targets for Antiparasitic Intervention

452 Pages·2014·10.24 MB·English

by  Christian Doerig

Drug Discovery in Infectious Diseases
Series Editor Paul M. Selzer
Volume 5
Protein Phosphorylation
in Parasites
Novel Targets for Antiparasitic Intervention
Edited by Christian Doerig, Gerald Späth,
and Martin Wiese

Editedby
ChristianDoerig, GeraldSp€ath,andMartinWiese
ProteinPhosphorylationinParasites
TitlesoftheSeries“DrugDiscoveryinInfectiousDiseases”
Selzer,P.M.(ed.) Caffrey,C.R.(ed.)
AntiparasiticandAntibacterial ParasiticHelminths
DrugDiscovery Targets,Screens,DrugsandVaccines
FromMolecularTargetstoDrug 2012
Candidates PrintISBN:978-3-527-33059-1,alsoavailable
asdigitalformat
2009
PrintISBN:978-3-527-32327-2,alsoavailable
Jäger,T.,Koch,O.,Flohé,L.(eds.)
inAdobePDFformatISBN:978-3-527-62682-3
Trypanosomatid Diseases
Becker,K.(ed.) MolecularRoutestoDrugDiscovery
ApicomplexanParasites 2013
MolecularApproachestowardTargeted PrintISBN:978-3-527-33255-7,alsoavailable
DrugDevelopment asdigitalformat
2011
PrintISBN:978-3-527-32731-7,alsoavailable
asdigitalformat
ForthcomingTopicsoftheSeries
GottfriedUnden,EckardThines,AnjaSchüffler(eds.)Antiinfectives
ChristianDoerig,GordonLangsley,PietroAlano(eds.)MalariaSignaling
RelatedTitles
Li,R.,Stafford,J.A.(eds.) Ghosh,A.K.(ed.)
KinaseInhibitorDrugs AsparticAcidProteasesas
2009 TherapeuticTargets
PrintISBN:978-0-470-27829-1,alsoavailable
2010
asdigitalformat
PrintISBN:978-3-527-31811-7,alsoavailable
asdigitalformat
Klebl,B.,Müller,G.,Hamacher,M.(eds.)
ProteinKinasesasDrug Smit,M.J.,Lira,S.A.,Leurs,R.(eds.)
Targets ChemokineReceptorsasDrug
2011 Targets
PrintISBN:978-3-527-31811-7,alsoavailable
2011
asdigitalformat
PrintISBN:978-3-527-32118-6,alsoavailable
asdigitalformat
€
Edited by Christian Doerig, Gerald Spath, and Martin Wiese
Protein Phosphorylation in Parasites
Novel Targets for Antiparasitic Intervention
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V
Contents
Foreword VII
Preface XI
ListofContributors XV
PartOne Bioinformatics 1
1 ComputationalAnalysisofApicomplexanKinomes 3
EricTalevich,NatarajanKannan,andDiegoMiranda-Saavedra(cid:1)
2 PhosphatomesofUnicellularEukaryoticParasites 37
AlexandraV.Andreeva(cid:1)andMikhailA.Kutuzov(cid:1)
PartTwo FunctionalAnalysisofParasiteKinomesandPhosphatomes 61
3 TrypanosomatidPhosphoproteomics 63
MichaelD.Urbaniak(cid:1)
4 TrypanosomatidCellDivisionKinases 79
CorinnaBenz,ElizabethThomas,andTansyC.Hammarton(cid:1)
5 KinetoplastidAGCKinases 99
SabineBachmaierandMichaelBoshart(cid:1)
6 PlasmodiumeIF2aKinases 123
DanielE.Goldberg(cid:1),MinZhang,andVictorNussenzweig(cid:1)
7 ProteinKinasesoftheParasiticProtistEntamoebahistolytica 131
Somlata,MrigyaBabuta,SudhaBhattacharya,andAlokBhattachary(cid:1)
8 ProteinPhosphatasesinTrypanosomeGrowth
andDevelopment 155
Bal(cid:1)azsSz€o(cid:1)o(cid:1)r(cid:1)andKeithR.Matthews
VIjContents
PartThree RoleofHostCellKinomesandPhosphatomesinParasitic
Infections 179
9 HijackingofHostCellSignalingbyTheileria 181
KerryWoods(cid:1),ConradvonSchubert,andDirkDobbelaere
10 TheRoleofHost-andParasite-EncodedKinasesinToxoplasma–Host
Interactions 199
IraJ.Blader(cid:1),GustavoArrizabalaga,andWilliamJ.SullivanJr
11 MacrophageKinasesinLeishmaniasis 217
MaheshKumarPadwal,UddipanSarma,RakiSudan,andBhaskarSaha(cid:1)
PartFour DrugDiscovery 235
12 SelectiveInhibitionofParasiteProteinKinases 237
JenniferD.Artz,AmyK.Wernimont,Linda.Y.Lin,MerhnazAmani,
MirelaNeculai,TanyaHills,andRaymondHui(cid:1)
13 KinaseInhibitorsAmongHitsfromMalariaCellularScreens 261
JamesR.Brown,DavidDrewry,Francisco-JavierGamo,
andJoseF.Garcia-Bustos(cid:1)
14 Calcium-DependentProteinKinasesofApicomplexanParasitesasDrug
Targets 293
KayodeK.Ojo,EthanA.Merritt,DustinJ.Maly,andWesleyC.VanVoorhis(cid:1)
15 ProteinKinasesasSuitableTargetsforCombatingEimeriaspp. 317
RichardJ.Marh€ofer,JeremyC.Mottram,andPaulM.Selzer(cid:1)
16 ReceptorTyrosineKinaseSignalingandDrugTargetinginSchistosomes 337
ColetteDissous(cid:1),MathieuVanderstraete,SvenjaBeckmann,Nad(cid:3)egeGouignard,
SilkeLeutner,ChristinBuro,andChristophG.Grevelding
17 ProteinKinasesasDrugTargetsintheTreatmentofAlveolar
Echinococcosis 357
KlausBrehm(cid:1)
18 CollaborativeDrugDesignofPlasmodiumKinaseInhibitors 375
BarryHardy(cid:1),RomanAffentranger,AlessandroContini,HugoGutierrezdeTeran,
JeffSpitzner,RubenPapoian,WilliamL.Seibel,SandraNelson,JeffreyWiseman,
SharonD.Bryant,IsabelleLucet,andChristianDoerig
Index 417
j
VII
Foreword:ProteinKinasesinParasites
Today, despite the fact that this is not obvious to the vast majority of the people
leaving in industrialized countries, a large part of the world is still massively
suffering and dying from parasitic diseases as a result of the lack of efficacious
and/or affordable treatments. Each year 30,000 people pass away due to human
AfricanTrypanosomiasis(HATorAfricansleepingsickness),adiseasecausedbythe
parasiteTrypanosomabruceispp.Availabletreatmentsforthisdiseasearepoor,with
unacceptable efficacy and safety profiles, particularly in the late phase of the
infection when the parasite has invaded the central nervous system. In South
andCentralAmerica,TrypanosomacruziistheinfectiousagentofChagas’disease
(AmericanTrypanosomiasis)whichrepresentsthemostimportantparasiticinfec-
tioninthispartoftheworld.Itisaffectingmorethan10millionpeople,withabout
100millionpeopleatrisk.Leishmaniasisisduetotheinfectionbyprotozoaofthe
genus Leishmania andisaffecting morethan10million peopleworldwide. These
parasitesliveinthealimentarytractofblood-suckingsandflies,andasnonflagellate
intracellular forms mostly within the macrophages of mammalian hosts. The
severity of the disease is ranging from cutaneous and/or mucosal to visceral
infection. Malaria occurs following infection by Plasmodium spp. and is the most
prevalentparasiticdisease,affectingmorethan250millionofpeopleperyearand
stillresponsibleforalmostamilliondeaths,thevastmajorityofwhichimpacting
childrenbelow5years.Notonlyunicellularparasitesbearahugeimpactonglobal
publichealth:parasitichelminths(worms),suchasSchistosomassp,alsorepresenta
serious public health problem, mostly in the developing world. In view of such a
dramaticsituation,morethanever,itiscrucialthattheentirescientificcommunity
inbasicresearchandindustriesdevelopsallpossiblestrategiesleadingtoanarsenal
of therapeutic weapons that will efficiently treat patients and eradicate these
diseases. Among possible drug targets, enzymes that modulate the level of phos-
phorylationofparasiteandhostproteinssuchasproteinkinases(PKs)andprotein
phosphatases are interesting candidates.
First,thekinomesofparasiteslikekinetoplastidsandapicomplexanscouldreveal
promisingtaxon-specificdrugtargets.Indeed,signallingpathwaysarewellknown
to allow any organism to adapt to its environment by coordinating intracellular
processes.Bioinformaticsapproachesrevealedatotalof176PKsinT.brucei,190in
VIIIjForeword:ProteinKinasesinParasites
T. cruzi and 199 in L. major. Compared to trypanosomatids, the human kinome
contains3timesmoreproteinkinaseswhilethesizeofthePlasmodiumkinomeis
only about half that of trypansomatids. Trypanosomatids and Plasmodium do not
contain receptor-linked tyrosine kinases, but possess divergent kinases with no
orthologues in the mammalian kinome (Ward P, Equinet L, Packer J, Doerig C.
2004. BMC Genomics; Parsons, M, Worthey E, Ward P, Mottram J. 2005. BMC
Genomics). The fact that trypanosomatids exhibit a large set of PKs, covering
approximately 2% of each genome, suggests that phosphorylation may play a key
role in the biology of most parasites.
Despite differences in kinome sizes and composition from one parasite to
another, major signalling pathways and functions are conserved. Motility, for
instance, is an essential attribute that allows some parasites finding their target
cellsinhumanhostsand/orarthropodvectors.Inapicomplexans,thiskeydriving
forcedependsonauniquecomponentwherebyadhesinscontainedinthemicro-
nemes are released onto the parasite apical extremity and translocated to the
posteriorendofthecell,thuspropellingtheparasiteforward.InToxoplasmagondii,
Calcium-dependentproteinkinase1(TgCDPK1)isanessentialregulatorofcalcium-
dependentexocytosisand thiscouldwellbethecaseinmostoftheopportunistic
humanparasites.Recently,thephosphorylationofthealphasubunitofeukaryotic
translation initiation factor 2(eIF2a)wasdescribed elevated indormant formsof
apicomplexanparasitessuchasPlasmodiumspp.andToxoplasmagondii.(ZhangM.
et al., Eukaryotic Cell, 2013).
Kinases have been shown to be essential for survival of parasites in their
mammalianhosts.Nevertheless,aparasitekinase-specificsmallmoleculeinhibitor
stillawaitstobeidentifiedandthequestionwhetherdruggingtheparasitekinomeis
moreadreamorarealitybegsforananswer.Incomplexparasitelifecyclessuchas
that of Plasmodium, most of the key developmental forms of the parasite such as
sexualandliverstagesrelyonproteinkinase-mediatedregulationsashighlightedby
C. Doerig (Nat. Chem. Biol.) commenting the work of Kato et al. who has
demonstrated that PfCDPK1 plays a key role in asexual blood stage egress.
Considering the 3-dimensional structure of protein kinases, there are increasing
evidencesthattheATP-bindingpocketrepresentsadruggablesite.Specifickinomes
like the one of Plasmodium display sufficient specificity, compared to the human
one, to represent a potentially fertile source of novel targets. Interestingly, the
counteractingbiochemicalreactionsdrivenbyPlasmodiumphosphatasesaresimi-
larly specific enough to envisage drug discovery programs targeting molecular
events that are modulated by these enzymes (Wilkes and Doerig BMC genomics
2008).
SincehelminthsareMetazoanandhavethereforeakinomethatisverysimilarto
that of their hosts, it is unlikely that highly selective targets will be identified.
However, the kinome still remains an attractive target in this case to: precisely
becauseofsimilaritiesbetweenthehelminthicandhumankinomes,“piggy-back”
approachesexploitingthewealthofresourcesdevotedtotargetinghumankinasesin
thecontextofdiseasessuchascancerandneurodegenerativediseasesisanattractive
option as a strategy to combat diseases caused by worms.