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#021095
Embargoed by the Journal of Molecular Biology,
X'riday,February 10, 1995
Scientistsat The ScrippsResearchInstitute DiscoverMechanismof Action of Drug Usedto
Treat Schistosrimiasis,
a Worldwide Health Problem
La Jolla,CA. February10, 1995- A teamof biophysicistsled by JohnTainer,Ph.D.,at The
ScrippsResearchInstitute,havereporteda discoveryin understanding
the mechanismof action
of the leadingdrugusedto treata parasiticworm diseasethat afflictsmorethan275 million
peopleworldwide,largelyin developingcountries.This finding may leadto the designof new
andmoreeffectivedrugsto treatthe disease.
Secondonly to malariain the numberof peopleit ef{ectsthroughoutthe world, schistosomiasis,
alsoknown as "snailfever,"is a lethalparasiticinfectionresponsible
for asmanyas200,000
deathsannually.Despitean increasein concertedeffortsto fight the disease,
the incidenceof
schistosomiasis
is increasing.
-- in which x-raysareprojectedthrough
Using a techniqueknown asx-ray crystallography
crystalsof pure protein to createa distinctivepatternthat canbe analyzedto measurethe exact
positionof eachatom-- the scientistsdeterminedthethree-dimensional
structureof oneof the
parasite'sdefensiveproteins,an enzymecalledglutathioneS-transferase.
The scientists'findings
show for the first time that the enzymqknown to be responsiblefor the elimination of many
toxins and crucial to the worm's survival,bindsto the drug praziquantelwhich is the drug of
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Page2 - Drug Usedto Treat Schistosomiasis
choice for the treatment of schistosomiasisand also is usedto treat other parasitic worm
infections.
According to Fred Cohen, M.D., Ph.D., in the Departmentof PharmaceuticalChemistry and
Medicine at the University of Califomia, San Francisco,"This is an important finding becauseit
identifies the molecular target for praziquantelwith atomic precision. This will help researchers
in their quest to make variants of the drug that may be more effective and less expensive,while
overcoming the problem of resistanceto the medication."
The study was published in the February 10 issueof the Journal of Molecular Biologt inan
article entitled, "Crystal Structuresof a SchistosomalDrug and Vaccine Target: Glutathione
S-Transferasefrom Schistosomajaponica and its Complex with the Leading Antischistosomal
Drug Praziquantel," by Michele A. McTigue, DeWight R. Williams and John A. Tainer.
"The binding of praziquantelto glutathione S-transferasesuggeststhat the drug may kill the
parasiteby inhibiting the enzyme which would causea lethal buildup of toxins within the
parasite," noted Tainer. "Knowing its atomic structur'ewith praziquantelbound may also allow
the design of new drugs for the treatmentof this debilitating disease,a situation made more
critical by the increasingreports of the parasitesbecoming resistantto known therapeutics."
As of 1991, the World Health Organizationrecognized76 nations as endemic for
schistosomiasis,including countries in Africa, Asia and the Far East, South America and the
Middle East. It is estimatedthat more than 400,000people with schistosomiasisare living in the
United Statestoday.
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Page3 - Drug Usedto Treat Schistosomiasis
The diseaseis causedby waterbomeSchistosomo
bloodflukes(a type of flatworm)that develop
in certainspeciesof snailsandthenexit the snailsto infecthumansby bunowingthroughtheir
skin while they arewading or swimming.Onceinsidethe humanbody, the worms maturein the
blood vesselsandthenproduceeggs,which canbe life-threatening
whenthey aretrappedin the
liver, bladder,brain or othervital organs.
Within endemiccountries,transmissionis mostintensein rural areaswhereinadequate
water
supplies,limited sanitationand frequenthumancontactwith freshwater arethe nonn. However,
transmissionhasoccurredin largecitiesin BraziIandAfrica. Symptomsof the diseaseinclude
high fever,abdominalpain,dianhea,weightloss,myalgia,arthralgia,andin severecases,renal
failure andcirrhosisof the liver.
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