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# 112993
Scripps Scientist DiscussesTechniquesand Strategiesfor Improving Developmentof
Catatytic Antibodies
Boston,Mass. November29, 1993-
DonaldHilvert, Ph.D., memberof the Deparfrnentof
Chemistryat The ScrippsResearchInstitutein La Jolla, Calif., discussedthe preparationof
antibodymoleculeswith tailoredcatalyticpropertiesat the symposium,"Biomolecular
Materialsby Design," sponsoredby the MaterialsResearchSocietyin Bostonthis week.
By current estimates,the immunesystemof mammals,man included,hasthe potentialto
generateat least 100 million different antibodymolecules,eachwith a distinctiveshape.This
capacityexiststo protectthe body againstdisease-causing
microorganismsand toxins, but
scientistshave learnedthat this remarkableprot'ein-generating
systemcan also be exploitedto
produceantibodyproteinswith enzymeactivity, or "catalyticantibodies."
It has beenknown for many yearsthat naturalenzymeshastentheir reactionsby selectively
binding and stabilizingmoleculesin their high energytransitionstates.The productionof
catalyticantibodiesexploitsthis principle of transitionstatestabilization.Stablemoleculesthat
mimic the essentialfeaturesof the relevanttransition stateare usedto generatean immune
response.The antibody binding pocketsthat are producedare complementaryin shapeto the
transition stateanalogin much the sameway a mold is complementaryin shapeto its
correspondingstatue.If the transitionstateanaloghasbeendesignedwell, theseantibodies
also catalyzethe targetreaction.
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Strategiesfor Improving Developmentof catalytic Antibodies
Using this approach,antibodycatalystshavebeenpreparedfor many classesof chemical
reaction, including reactionsthat are difficult or impossibleto carry out using conventional
chemistry.Moreover, becauseboth the synthesisof transitionstateanalogsand the production
of antibodiesare routinetechniques,theseagentscan be producedin the courseof a relatively
short laboratory experiment,in contrastto natural enzymeswhich have evolved over many
millions of years.
Consequently,accordingto Hilvert, "This technologyputs at our fingertipsthe meansto
createentirely new enzymesfor use in researchtools and also in medicineand industry." For
example,it might be possibleto preparecatalyticantibodiesthat can cut throughviral coat
proteins,deactivatetoxic chemicals,or repair DNA damagecausedby exposureto solar
ultraviolet radiation.Catalyticantibodiesmight also be usedsomedayin enzymereplacement
therapiesto treat humangeneticdiseases.Alternatively,they may makethe productionof
many valuablepharmaceuticals
cheaperand more efficient than is possiblewith currently
availablemethods.
Hilvert's discussionhighlightedthe preparation.ofcatalyticantibodiesfor reactionsinvolving
the formation of carbon-carbon
bonds.Suchreactionsare importantin the constructionof
many useful molecules,from relativelysimplecommoditychemicalsto novel polymeric
materials and denselyfunctionalizednatural productsand therapeuticagents.However, they
are often difficult to carry out with high ratesand high selectivity in the laboratory. Hilvert
describedthe basic strategiesfor designingeffectivetransitionstateanalogsfor thesereactions
as well as the propertiesof the resulting catalysts.
Knowledge gained in the courseof thesestudiesis expectedto guide future efforts to
capitalizeon the immunesystem's"hidden"capacityfor catalysis.
Becauseantibodiesare biocompatiblemolecules,they can be usedin principle to carry out
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Strategiesfor Improving Developmentof catalytic Antibodies
reactionsin living cells. The teamled by Hilvert hasdemonstrated
that this is indeedthe
case,showingthat an antibodytl:o;tcatzlyzesa metabolicallyessentialreaction- the
conversionof chorismateinto prephenate- is catalyticallyactivein yeastcells and can, to a
limited degree,replacethe activity of the natural enzymethat normally carries out this
reaction.Theseexperimentsshow "that eukaryoticcells can be directedto produceman-made
catalystsnot normally found in their evolutionaryrepertoire." This ability could provide
scientistswith a new tool for regulatingcellular function, alteringcellular metabolism,and
destroyingtoxins in vivo.
Progressin the field of antibodycatalysishasbeenrapid since 1986when theseagentswere
first described.Not only do catalyticantibodiesexhibit atl the propertiesof enzymes,
including substantialrate accelerations,and exactingsubstratespecificitiesand selectivities,
but they appearto achievetheseeffects via mechanismssimilar to thoseof their naturallyoccurring counterparts.The challengefor the future will be to expandthe repertoire of
reactionsthat can be acceleratedwith immunoglobulinsand to increasethe chemical
efficiency of the first-generationcatalysts.Modern molecularbiologicaltechniqueswhich
allow the expressionand engineeringof individual antibodiesand which provide greater
accessto the full diversity inherentwithin the immunologicalrepertoire,togetherwith
powerful geneticscreensand selections,will greatlyfacilitatetheseefforts. The field of
catalyticantibodiesis inherentlymultidisciplinary;by successfullyintegratingchemistryand
immunologywith molecularbiology and geneticsan evenmore versatilepaletteof catalysts
for practicalapplicationsin chemistry,biology and medicinemay becomeavailable.
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