Design of substrate-based inhibitors of human beta-secretase

J Med Chem. 2002 Jan 17;45(2):259-62. 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.

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Brain / enzymology
  • Endopeptidases
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Humans
  • Models, Molecular
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Enzyme Inhibitors
  • Oligopeptides
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE2 protein, human
  • BACE1 protein, human