Memapsin 2 (beta-secretase, BACE) is the protease that initiated the cleavage of beta-amyloid precursor protein (APR) leading to the production of amyloid-beta (Abeta). It is the major target for the development of inhibitor drugs against Alzheimer's disease (AD). The understanding on the activity, structure and function of memapsin 2 is fundamental for inhibitor design and testing. During the last 5 years of this project, we have established assays, completed kinetic specificity analysis, determined crystal structures and designed generations of inhibitors that have attained high potency, relatively small size, and good selectivity vs. chosen human aspartic proteases, cell permeability and inhibition of Abeta production in transgenic AD mice. For the next period of this project, we propose to further probe memapsin 2 for structure-function information relevant to inhibitor development, to acquire better drug-like properties, to explore new chemistry for inhibitor synthesis and to develop non-transition state inhibitors against newly discovered subsites of memapsin 2.
The Aims are:
Aim 1. To carry out in-depth memapsin 2 structure-function studies for further structure-based inhibitor design. We propose to investigate the binding affinity of new ligands toward memapsin 2 subsites S7, S6 and S5, the role of active-site cleft 'bottleneck'residues on the inhibitor subsite specificity, cellular inhibition by memapsin 2 inhibitors and the therapeutic limits of memapsin 2 inhibitor drugs.
Aim 2. Design and testing transition-state memapsin 2 inhibitors with better in vivo potency and selectivity. We propose to optimize ligand-binding site interactions of lead peptidomimetic inhibitors, design and synthesize novel nonpeptidyl high-affinity ligands, templates and scaffolds, incorporate basic amines and lipophilic functionalities for effective absorption and BBB transport, and improve potency of small molecule nonpeptidyl inhibitors.
Aim 3. To develop and test novel memapsin 2 inhibitors targeting to new sites in the protease. We propose to design and test a new class of non-transition state inhibitors targeted at 3 unique subsites, P7, P6 and P5. We will use structure-based design cycle to develop small, potent and selective new inhibitors.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CDIN-D (01))
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Buckholtz, Neil
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Oklahoma Medical Research Foundation
Oklahoma City
United States
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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; Venkateswara Rao, Kalapala; Yadav, Navnath D et al. (2012) Structure-based design of highly selective ýý-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure. J Med Chem 55:9195-207
Ghosh, Arun K; Brindisi, Margherita; Tang, Jordan (2012) Developing ýý-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 ýý-secretase inhibitors. Bioorg Med Chem Lett 22:5460-5
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
Ghosh, Arun K (2010) Capturing the essence of organic synthesis: from bioactive natural products to designed molecules in today's medicine. J Org Chem 75:7967-89

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