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.
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