The overall objectives of this proposal are to elucidate the mechanism of action of different classes of next generation ?-secretase modulators (GSMs), to determine their synergistic effect, and to apply them in examining the role of A?42, A?38 and A?37 in amyloid pathology, synaptic plasticity and learning and memory. The development of GSMs that suppress ?-secretase activity for A?42 production and yet do not affect overall APP processing and cleavages of other substrates has emerged as a promising strategy for AD therapy. Progress in the development of these clinical candidates depends on a deeper understanding of the drug-target interactions. To this end we propose to map the binding site of acid GSMs within the ?-secretase complex and to investigate the structural basis of ?-secretase modulation. Additionally, we will determine the mechanism of cooperatively between the ?-secretase active site and the imidazole based GSM binding site(s). Finally, we will examine the synergistic effect of two classes of GSMs in cellular and animal models with a focus on safety, synaptic plasticity and learning and memory. The proposed research will provide mechanistic insights into GSM modulation of ?-secretase, the function of A? in disease and new therapeutic strategies, shaping our understanding of GSM selectivity and advancing our ability to design effective treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS096275-03
Application #
9487034
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
2016-06-01
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Fried, Eric S; Li, Yue-Ming; Gilchrist, M Lane (2017) Phase Composition Control in Microsphere-Supported Biomembrane Systems. Langmuir 33:3028-3039
Gertsik, Natalya; Am Ende, Christopher W; Geoghegan, Kieran F et al. (2017) Mapping the Binding Site of BMS-708163 on ?-Secretase with Cleavable Photoprobes. Cell Chem Biol 24:3-8
Frost, Georgia R; Wong, Eitan; Li, Yue-Ming (2017) Versatility of presenilin 1. Proc Natl Acad Sci U S A 114:6885-6887
Crump, Christina J; Murrey, Heather E; Ballard, T Eric et al. (2016) Development of Sulfonamide Photoaffinity Inhibitors for Probing Cellular ?-Secretase. ACS Chem Neurosci 7:1166-73
Gertsik, Natalya; Chau, De-Ming; Li, Yue-Ming (2015) ?-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of ?-Secretase and Signal Peptide Peptidase. ACS Chem Biol 10:1925-31