Design of Substrate-Based Inhibitors of
Human β-Secretase

Tung, Jay S.; Davis, David L.; P. Anderson, John; Walker, Don E.; Mamo, Shumeye; Jewett, Nancy; Hom, Roy K.; Sinha, Sukanto; Thorsett, Eugene D.; John, Varghese

doi:10.1021/jm0155695.s003

Design of Substrate-Based Inhibitors of Human β-Secretase

journal contribution

posted on 2001-12-20, 00:00 authored 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.