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Designer chemical offers Alzheimer's hope

Researchers at the University of Illinois at Chicago have designed and synthesized highly potent inhibitor compounds that could lead to an effective treatment for Alzheimers disease. The work was reported in the American Chemical Societys Journal of Medicinal Chemistry.

Arun Ghosh, professor of chemistry, led the UIC research team in collaboration with Jordan Tang, head of the Protein Studies department at the Oklahoma Medical Research Foundation in Oklahoma City.

In earlier work, Ghosh and Tang designed an inhibitor that blocks the action of one of two protein-cutting enzymes, called proteases, thought to be responsible for Alzheimers disease. This enzyme, called memapsin 2, severs a longer protein in the brain called amyloid precursor protein, or APP, to produce beta-amyloid, which accumulates in the brain and forms plaques that lead to the development of Alzheimers disease.

This enzyme is probably the most exciting target for an Alzheimers drug, said Ghosh.

Tang discovered the precise location where memapsin 2 cuts APP. Subsequently, Tang and Ghosh demonstrated that a model inhibitor compound attracts memapsin 2 and keeps it from cutting APP a promising way to halt accumulation of beta-amyloid in the brain. That inhibitor was reported in the Journal of the American Chemical Society last year and was shown to be effective in test tube experiments.

The research team knew that while useful as a model, the inhibitor would not be effective in drug therapy. That was a preliminary inhibitor, said Ghosh. Its a big one, containing eight peptides a size that is inconceivable to be a drug candidate.

Ghosh and his team set out to reduce the molecules size in an effort to increase its potential as a drug candidate.

Peptide-like compounds never make useful drugs because theyre metabolically unstable, theyre insoluble and, perhaps the biggest problem in Alzheimers patients, theyre hard to deliver in the human brain
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Contact: Paul Francuch
francuch@uic.edu
312-996-3457
University of Illinois at Chicago
2-Aug-2001


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