Researchers from the nucleotide pharmaceutical companyGilead Sciences Inc. have demonstrated for the first time thethree-dimensional structure of a molecule created throughdirected evolution.

Their report was published in Tuesday's issue of Biochemistry.

Collaborators at Wesleyan University determined the novelDNA molecule is shaped like a chair or throne. Chemistryprofessor Philip Bolton identified the shape of the 15-subunitstrand with state-of-the-art nuclear magnetic resonance andcomputer modeling.

The molecule, GS 522, has shown potent anti-coagulant activityin animal studies. Gilead will use information about itsstructure to develop more potent coagulation inhibitors.

Heparin, the most commonly used drug to inhibit bloodcoagulation, remains in the bloodstream two to three days,creating a risk of internal bleeding. GS 522 is active a muchshorter time, diminishing this risk.

"They're on the cutting edge of test-tube evolution," said TimWilson, an analyst with Hambrecht & Quist.

Gilead (NASDAQ:GILD, a Foster City, Calif., companyincorporated in 1987, published a paper a year ago in Naturedescribing how the company mimicked the steps of evolutionto rapidly find a molecule shaped to bind the key blood-clotting protein thrombin and deactivate the enzyme. Such amolecule would be potentially useful to inhibit clotting duringbypass surgery.

Gilead's scientists randomly synthesized 10 trillion differentchains, said Michael Riordan, president and chief executiveofficer, that were sufficiently varied to have a few chains withthe right shape to bind thrombin. The best candidate wasselected through affinity chromatography.

The technique is medicinal chemistry, not genetic engineering,because the DNA is just providing conformation and the abilityto create hydrogen bonds with the enzyme in question. Theprocess is also a potentially quick way to develop promisinglead compounds.

"Essentially, we made a leap of discovery and supposed itwould be possible for DNA to create shapes never seen before,"Riordan told BioWorld. The shapes are called "aptamers" fortheir ability to aptly fit the desired target.

Gilead also uses nucleotide chemistry to develop smallmolecules of one to three subunits to inhibit viral enzymessuch as cytomegalovirus (CMV), which causes sight-threateningeye infections in AIDS patients, and to create code-blockers,such as antisense molecules, to block the activity of specificgenes.

Nucleotide technology "could be a whole new way to do drugdiscovery," Wilson said, noting the Biochemistry article"provides support for their aptamer technology."

The Biochemistry article also suggests that DNA can form amuch greater variety of stable shapes than previouslysuspected.

-- Nancy Garcia Associate Editor

(c) 1997 American Health Consultants. All rights reserved.

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