Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain. Amyloid plaques are composed of Beta-amyloid peptides (Abeta), which are produced when amyloid precursor protein (APP) is cleaved by Beta-secretase, and then followed by Gamma-secretase cleavage. Gamma-secretase complexes cleave APP differentially generating two products, Abeta40 and Abeta42, the putatively more toxic species. According to the """"""""amyloid cascade hypothesis,"""""""" Abeta forms a neurotoxic species that triggers a pathological cascade that leads to neurodegeneration. Therefore, therapies that reduce Beta-amyloid peptides, especially Abeta42, may provide effective treatment of AD. Through detailed biochemical characterization, this study aims to: 1) Synthesize distinct photoreactive, peptidomimetic g-secretase inhibitors which will help isolate the active site proteins of g-secretase, 2) Identify novel proteins that putatively contribute to the active site of g-secretase, and 3) Validate and characterize identified proteins related to g-secretase activity. These investigations will facilitate the development of selective gamma-secretase inhibitors for the treatment of Alzheimer's disease. ? ?
| Shelton, Christopher C; Zhu, Lei; Chau, Deming et al. (2009) Modulation of gamma-secretase specificity using small molecule allosteric inhibitors. Proc Natl Acad Sci U S A 106:20228-33 |
| Yang, Guangli; Yin, Ye Ingrid; Chun, Jiong et al. (2009) Stereo-controlled synthesis of novel photoreactive gamma-secretase inhibitors. Bioorg Med Chem Lett 19:922-5 |
| Shelton, Christopher C; Tian, Yuan; Shum, David et al. (2009) A miniaturized 1536-well format gamma-secretase assay. Assay Drug Dev Technol 7:461-70 |
