Oklahoma City, OK – Researchers at the Oklahoma Medical Research Foundation and 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.
Jordan Tang, Ph.D., head of the Protein Studies department at OMRF led the team in collaboration with Arun Ghosh, Professor of Chemistry at UIC. OMRF scientists who contributed to the paper include: Lin Hong, Ph.D., Jeffrey A. Loy, Ph.D., and Gerald Koelsch, Ph.D. Jacques Ermolieff, Ph.D. and Chan Ngyuen, both formerly of OMRF, were also authors of the paper.
Earlier, teams lead by Tang and Ghosh designed an inhibitor which blocks the action of one of two protein-cutting enzymes, called proteases, thought to be responsible for Alzheimer’s disease. The targeted enzyme, called memapsin 2, cuts a longer brain protein called amyloid precursor protein, or APP. The resulting byproduct, or beta-amyloid, accumulates in the brain, forming plaques and leads to the development of Alzheimer’s disease.
In the current paper, a new generation of inhibitors has been designed and tested in the laboratory. These new inhibitors are smaller and yet still quite potent. “Designing a smaller, more potent inhibitor is an important step in the development of an effective medicine for the treatment of Alzheimer’s patients,” said Tang.
In 2000, Tang’s team discovered that memapsin 2 cuts APP to initiate the process leading to Alzheimer’s disease. Subsequently, Tang and Ghosh demonstrated that a model inhibitor compound attracts memapsin 2 and keeps it from cutting APP, thereby halting the accumulation of beta-amyloid. That inhibitor was publicly reported in the Journal of the American Chemical Society last year and was shown to be effective in test tube experiments.
However, the research team knew that while useful as a model, the original inhibitor would not be effective in potential drug therapy. “That was a preliminary inhibitor,” said Ghosh. “It’s a big one, containing 8-residues, a size that is inconceivable to be a drug candidate.”
In the October 6, 2000 edition of Science, OMRF and UIC scientists reported the determination of the three-dimensional structure of memapsin 2 bound to an inhibitor that defined the location of eight subsites. This structure provided a model for the design and testing of the new generation of inhibitors.
“We have taken a significant step forward,” said Tang about the new inhibitors. “We are closer to having an inhibitor that can be used in drug therapy to treat Alzheimer’s disease.”