Researchers at the University of Illinois at Chicago have designed and synthesized highly potent inhibitor compounds that could lead to an effective treatment for Alzheimer's disease. The work was reported in the American Chemical Society's 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 Alzheimer's 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 Alzheimer's disease.
"This enzyme is probably the most exciting target for an Alzheimer's 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. "It's 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 molecule's size in an effort to increase its potential as a drug candidate.
"Peptide-like compounds never make useful drugs because they're metabolically unstable, they're insoluble and, perhaps the biggest problem in Alzheimer's patients, they're hard to deliver in the human brain," Ghosh said. The molecule has to be small enough to cross what's called the blood-brain barrier. "Peptide-like molecules are not very good at penetrating this barrier. Our ultimate goal is to deliver a totally non-peptide inhibitor," he said.
The current paper describes a new generation of inhibitors designed and tested in the laboratory. These new inhibitors are still potent yet substantially smaller, comparable in size to HIV protease inhibitor drugs now being prescribed.
"Designing a smaller, more potent inhibitor is an important step in the development of an effective treatment for Alzheimer's patients," said Tang.
The research is supported by grants from the National Institutes of Health.
The Alzheimer's Association reports about 4 million Americans now suffer from the disease. It predicts that number will grow as the population ages, unless a cure or prevention is found. Current treatments provide only symptomatic relief.