Design of substrate-based inhibitors of human beta-secretase

  • J Med Chem. 2002 Jan 17;45(2):259-62. doi: 10.1021/jm0155695.
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
PMID: 11784130 DOI: 10.1021/jm0155695
Abstract

By use of the effectively cleaved Beta-secretase (BACE) substrate (1), incorporation of a statine in P(1) resulted in a weak inhibitor 13 of the enzyme. Further substitution of P(1)'-Asp by P(1)'-Val in 13 results in a potent inhibitor 22 of BACE. Removal of the P(10)-P(5) 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.