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Design of Substrate-Based Inhibitors of Human β-Secretase

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journal contribution
posted on 20.12.2001, 00:00 by Jay S. Tung, David L. Davis, John P. Anderson, Don E. Walker, Shumeye Mamo, Nancy Jewett, Roy K. Hom, Sukanto Sinha, Eugene D. Thorsett, Varghese John
By use of the effectively cleaved β-secretase (BACE) substrate (1), incorporation of a statine in P1 resulted in a weak inhibitor 13 of the enzyme. Further substitution of P1‘-Asp by P1‘-Val in 13 results in a potent inhibitor 22 of BACE. Removal of the P10−P5 residues on the N-terminal part of inhibitor 22 resulted in no loss of potency (23). C-terminal truncations of inhibitor 22 generally led to significant loss of potency.