Drug Discovery

Anti-amyloid

Helical Peptidomimetics as Inhibitors of Alzheimer's gamma-Secretase

Investigator(s): Michael S. Wolfe, Ph.D., Associate Professor of Neurology

Institution(s): Brigham & Women's Hospital, Harvard Medical School, Boston, MA

Duration: 2000 - 2001

Summary:

The grant will fund research aimed at producing inhibitors of gamma-secretase, one of two enzymes responsible for the production of ß-amyloid. gamma-secretase inhibitors developed in this laboratory are being used extensively by those working in the field. Dr. Wolfe proposes a number of novel approaches to drug discovery in his application. His group will target a specific active site on the gamma-secretase enzyme to develop new peptide drugs. These peptides will be modified to form a special conformation (helical) which will allow them to interact more efficiently with the gamma-secretase enzyme. A new peptide has already been identified. The proposed study aims to discover more potent analogues of the new peptide already identified. These compounds will be studied to assess their ability to block ß-amyloid production in cells. This work will be carried out in collaboration with Dr. Dennis Selkoe, a leading figure in Alzheimer's research. Once identified, lead analogues will then be optimized to enhance their activity and stability. Active compounds developed in this project will enhance knowledge of gamma-secretase as a drug discovery target for reducing ß-amyloid production and may potentially be useful for commercial development.