Targets for drug design in Targets for drug design in schistosome parasitismschistosome parasitism

Presented by:Presented by:

Prof. Afaf El-AnsaryProf. Afaf El-Ansary

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).

SchistosomesSchistosomes

Molluscan Snail HostsMolluscan Snail Hosts Definitive Human HostsDefinitive Human Hosts

- -BiomphalariaBiomphalaria ( ( S.mansoniS.mansoni))---BulinusBulinus ( (S.haematobiumS.haematobium)

Schistosome Life CycleSchistosome Life Cycle

Control of SchistosomiasisControl of Schistosomiasis

Health educationHealth education

Snail controlSnail control Vaccine developmentVaccine development

DrugsDrugs ((PraziquentelPraziquentel))

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

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

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)

High Ca++

Low Ca++

Adult WormAdult Worm TargetsTargets

Sm GynecophoralSm Gynecophoral ProteinProtein

Sm Fatty acidsSm Fatty acids BindingBinding ProteinProtein

Glucose uptakeGlucose uptake Host immunityHost immunity

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

Host immunityHost immunity

SmSm Glutathione peroxidase and Glutathione peroxidase and SmSm peroxidoxins peroxidoxins

TNF-TNF-

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

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

Molluscan snail hostsMolluscan snail hosts

Strong cellularStrong cellular reactionsreactions

Non-SusceptibleNon-Susceptible

PhysiologicallyPhysiologically unsuitableunsuitable

Parasite killingParasite killing

No cellular No cellular reactionsreactions

SusceptibleSusceptible

PhysiologicallyPhysiologicallysuitablesuitable

Intra molluscanIntra molluscanStage targetStage target

SerotoninSerotonin receptorsreceptors

SchistosominSchistosomin Phenol-oxidasePhenol-oxidaseSnail’s glycolyticSnail’s glycolytic

enzymesenzymes

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