Aug. 24, 1998
Contact: Leila Belkora (312) 996-3457; [email protected]
Editors: Embargoed until noon E.S.T., Aug. 25
UIC CHEMIST DEVELOPS SYNTHESIS OF HIV-FIGHTING MOLECULE
University of Illinois at Chicago chemist Arun K. Ghosh will present an effective molecule-building technique that may lead to enhanced and less expensive treatment for HIV at the annual meeting of the American Chemical Society in Boston, Aug. 23-28. The technique is a new way for chemists to produce the core part of the protease inhibitor drug molecule in the laboratory. It may offer drug manufacturers a more cost-effective way to produce protease inhibitors and the possibility of modifying the drugs' basic structure to further improve their effectiveness against disease or to overcome drug resistance. Ghosh emphasized, however, that drug manufacturers have not yet evaluated the technique. Protease inhibitors are one type of drug that prevents the human immunodeficiency virus (HIV) from successfully replicating itself and spreading from cell to cell. Protease inhibitors act by attaching to the protease enzyme and preventing it from doing its job, which is to cut newly-manufactured virus proteins emerging from an infected cell into active pieces. Ghosh and his colleagues, graduate student Dongwoo Shin and postdoctoral researcher Packiarajan Mathivanan, focussed their efforts on an important segment of the drug molecule. "The key challenge of synthesizing protease inhibitors is to make the core structure," said Ghosh. "Most of the current protease inhibitors are derived from the so-called peptide isosteres. The problem is, the cores of the drug molecules consists of numerous asymmetric centers; they're stereochemically quite complex." The asymmetric centers are clusters of atoms within the molecule that have a particular orientation, or "chirality." Just as gloves come in left-handed and right-handed forms, although they each have four fingers and a thumb, chiral centers have the same atoms arranged differently. A center's chirality affects the molecule's biological activity.
To introduce the chiral centers and to synthesize the dipeptide isosteres with the minimum amount of chemical reagent - and hence most cost-effectively - Ghosh uses a catalyst developed by Scripps Institute researcher Barry Sharpless.
"The catalyst is very efficient; one catalyst molecule can produce many molecules of the desired product," said Ghosh.
In addition to producing large quantities of the protease inhibitor molecule cheaply, Ghosh's synthesis may help drug manufacturers by giving them a tool to combat drug resistance and a possible solution to the problem of drugs breaking down in the patient's stomach or intestines before being absorbed in the body.
"Most syntheses of the peptide isosteres are derived from amino acids, and there are only 20 amino acids, so that approach is limited to amino acid-derived substituents in the peptide isosteres," said Ghosh. "With our synthesis, one can now can change virtually every chiral center and design substituents of the isosteres to fit the enzyme active pocket more effectively."
That means researchers can use the new technique to replace some of the molecules' peptide bonds, which break down in stomach acid.
Drug resistance develops when mutations change the enzyme that the protease inhibitor acts on. The changes may make it harder for the drug to "lock on" to its target. Ghosh said researchers could use his technique to design and synthesize protease inhibitors that are effective against mutated forms of the viral enzyme.
"Research along this line is very critical for the future of anti-AIDS therapy," said Ghosh. "We are very grateful that the National Institutes of Health has provided funding for our investigations."
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