The applicant's laboratory has recently cloned beta-secretase, named memapsin 2 (M2). This is a key human brain aspartic protease involved in the production of Abeta from the amyloid precursor protein (APP) and the development of Alzheimer's disease (AD). In this proposal, Dr Tang plans to develop M2 inhibitors for the treatment of Alzheimer's disease. The applicant has extensive experience and success in the development of aspartic protease inhibitor drugs for the treatment of HIV infection, and their penetration through the blood brain barrier. Two prototype M2 inhibitors developed in the applicant's laboratory show a potent inhibitory effect. This proposal is focused on two main objectives; 1) to acquire the necessary information on M2 to develop inhibitor design, and 2) to design and test M2 inhibitors with a therapeutic potential. For attaining the first objective, M2 substrate specificity will be determined, M2 containing vesicles will be isolated from cells, x-ray crystal structure of M2 and M2-inhibitor complexes will be obtained, and the human and mouse M2 will be compared to validate the testing of M2 inhibitors in PDAPP transgenic mice. For the second Aim, a random-residue transition-state inhibitor library will be screened to determine M2 residue preferences for inhibition and to design small sized, potent inhibitors. These inhibitors will be tested in enzymatic, cellular and animal models. The M2 studies and inhibitor testing will be done in the applicant's laboratory. The Co-Investigator Dr Ghosh will do synthesis of inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018933-02
Application #
6509954
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Buckholtz, Neil
Project Start
2001-03-15
Project End
2006-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$441,740
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Ghosh, Arun K; Ghosh, Koena; Brindisi, Margherita et al. (2018) Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand. Bioorg Med Chem Lett 28:2605-2610
Ghosh, Arun K; Reddy, Bhavanam Sekhara; Yen, Yu-Chen et al. (2016) Design of Potent and Highly Selective Inhibitors for Human ?-Secretase 2 (Memapsin 1), a Target for Type 2 Diabetes. Chem Sci 7:3117-3122
Ghosh, Arun K; Brindisi, Margherita; Yen, Yu-Chen et al. (2015) Structure-based design, synthesis and biological evaluation of novel ?-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand. Bioorg Med Chem Lett 25:668-72
Coughlan, Kathleen; Huang, Xiangping; He, Xiangyuan et al. (2013) Expression and processing of fluorescent fusion proteins of amyloid precursor protein (APP). Biochim Biophys Acta 1833:1562-71
Li, Xiaoman; Hong, Lin; Coughlan, Kathleen et al. (2013) Structure-activity relationship of memapsin 2: implications on physiological functions and Alzheimer's disease. Acta Biochim Biophys Sin (Shanghai) 45:613-21
Ghosh, Arun K; Brindisi, Margherita; Tang, Jordan (2012) Developing ?-secretase inhibitors for treatment of Alzheimer's disease. J Neurochem 120 Suppl 1:71-83
Ghosh, Arun K; Pandey, Satyendra; Gangarajula, Sudhakar et al. (2012) Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent ?-secretase inhibitors. Bioorg Med Chem Lett 22:5460-5
Ghosh, Arun K; Venkateswara Rao, Kalapala; Yadav, Navnath D et al. (2012) Structure-based design of highly selective ?-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure. J Med Chem 55:9195-207
Chang, Wan-Pin; Huang, Xiangping; Downs, Deborah et al. (2011) Beta-secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J 25:775-84
Li, Xiaoman; Bo, Huang; Zhang, Xuejun C et al. (2010) Predicting memapsin 2 (?-secretase) hydrolytic activity. Protein Sci 19:2175-85

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