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Targets for drug design in Targets for drug design in schistosome parasitismschistosome parasitism
Presented by:Presented by:
Prof. Afaf El-AnsaryProf. Afaf El-Ansary
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SchistosomiasisSchistosomiasis
It is a chronic disease that affects more than 200 millionIt is a chronic disease that affects more than 200 million
people in 74 troplical and subtropical countries, and people in 74 troplical and subtropical countries, and
over 500 million people are estimated to be at risk ofover 500 million people are estimated to be at risk of
Schistosomiasis (WHO, 2005).Schistosomiasis (WHO, 2005).
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SchistosomesSchistosomes
Molluscan Snail HostsMolluscan Snail Hosts Definitive Human HostsDefinitive Human Hosts
- -BiomphalariaBiomphalaria ( ( S.mansoniS.mansoni))---BulinusBulinus ( (S.haematobiumS.haematobium)
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Schistosome Life CycleSchistosome Life Cycle
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Control of SchistosomiasisControl of Schistosomiasis
Health educationHealth education
Snail controlSnail control Vaccine developmentVaccine development
DrugsDrugs ((PraziquentelPraziquentel))
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Success in the control of the disease is Success in the control of the disease is usually measured byusually measured by::
Inhibition of cercarial penetrationInhibition of cercarial penetration
Decreased worm burden (liver & intestinal)Decreased worm burden (liver & intestinal)
Reduced egg countReduced egg count
Reduced number and diameter of granulomaReduced number and diameter of granuloma
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Cercarial penetration of mammalian Cercarial penetration of mammalian skinskin
Cercarial targetsCercarial targets
SmSm Stathmin Stathmin--
Like proteinLike protein
TryptophanTryptophan hydroxylasehydroxylase
CaCa++++-binding -binding protein 28KDaprotein 28KDa
ElastaseElastase
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Role of CalciumRole of Calcium
Prevent damage of cercarial membranePrevent damage of cercarial membrane
Enhance tail lossEnhance tail loss
Prevent dispersal of glycocalyx ( i.e. delay Prevent dispersal of glycocalyx ( i.e. delay presentation of antigens)presentation of antigens)
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High Ca++
Low Ca++
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Adult WormAdult Worm TargetsTargets
Sm GynecophoralSm Gynecophoral ProteinProtein
Sm Fatty acidsSm Fatty acids BindingBinding ProteinProtein
Glucose uptakeGlucose uptake Host immunityHost immunity
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Glucose transporterGlucose transporter
SGTP1SGTP1
SGTP2SGTP2
SGTP4SGTP4
SGTPSGTP44 transports glucose from the bloodstream transports glucose from the bloodstreamthrough the apical double bilayer membranethrough the apical double bilayer membrane
into the tegumentinto the tegument
Diagramatic representation of glucose movement Diagramatic representation of glucose movement through the tegument through the tegument..
Teg
um
ent
Teg
um
ent
SGTPSGTP11 transports glucose through transports glucose through the single lipid bilayer membranethe single lipid bilayer membrane
into the inner tissuesinto the inner tissues
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Host immunityHost immunity
SmSm Glutathione peroxidase and Glutathione peroxidase and SmSm peroxidoxins peroxidoxins
TNF-TNF-
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SmSm Glutathione peroxidase Glutathione peroxidase
SpecificSpecific activity of glutathione peroxidase during activity of glutathione peroxidase during developmental stages of schistosomes demonstrating developmental stages of schistosomes demonstrating higher activities in the extract of adult worms than in higher activities in the extract of adult worms than in the larval stages. the larval stages.
.…… .……Cumene Cumene hydroperoxidehydroperoxide
______ ______HH22OO22
Sp
ecif
ic a
ctiv
ity
(un
its
mg-1
)
0
5
10
15
20
25
30
35
Cer 3h 7 days 15 days 30 days 42 days
Developmental Stages
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TNF-
?
Cell membrane
Kinase Cascade 1
Increased Fecundity of Schistosome worm
PLC
Ceramide
DAG
Ceramide
A-SMase
Kinase Cascade 2
Schistosomula Death
2
+
+
+
+
+
1N-SMase
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Molluscan snail hostsMolluscan snail hosts
Strong cellularStrong cellular reactionsreactions
Non-SusceptibleNon-Susceptible
PhysiologicallyPhysiologically unsuitableunsuitable
Parasite killingParasite killing
No cellular No cellular reactionsreactions
SusceptibleSusceptible
PhysiologicallyPhysiologicallysuitablesuitable
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Intra molluscanIntra molluscanStage targetStage target
SerotoninSerotonin receptorsreceptors
SchistosominSchistosomin Phenol-oxidasePhenol-oxidaseSnail’s glycolyticSnail’s glycolytic
enzymesenzymes
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Callistemon lanceolatusCallistemon lanceolatus
Inhibition of glycolytic enzymesInhibition of glycolytic enzymes (HK, PK, PGI)(HK, PK, PGI)
Less compatible snails (Less adapted to anaerobiosis)Less compatible snails (Less adapted to anaerobiosis)
Reduced number of attenuated cercariaeReduced number of attenuated cercariae
Fail to penetrateFail to penetrate Able to penetrate human skinAble to penetrate human skin
Less pathogenicLess pathogenic
Sublethal concentrationSublethal concentration (LC25 and LC10)(LC25 and LC10)
Reduced worm burdenReduced worm burden
Reduced egg countReduced egg count
Less No and small diameter granulomasLess No and small diameter granulomas
Solanum nigrumSolanum nigrum