Structure-based design: potent inhibitors of human brain memapsin 2 (beta-secretase)

J Med Chem. 2001 Aug 30;44(18):2865-8. doi: 10.1021/jm0101803.

Abstract

Memapsin 2 (beta-secretase) is one of two proteases that cleave the beta-amyloid precursor protein (APP) to produce the 40-42 residue amyloid-beta peptide (Abeta) in the human brain, a key event in the progression of Alzheimer's disease. On the basis of the X-ray crystal structure of our lead inhibitor (2, OM99-2 with eight residues) bound to memapsin, we have reduced the molecular weight and designed potent memapsin inhibitors. Structure-based design and preliminary structure-activity studies have been presented.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Crystallography, X-Ray
  • Drug Design
  • Endopeptidases
  • Humans
  • Models, Molecular
  • Molecular Weight
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Structure-Activity Relationship

Substances

  • OM99-2
  • Oligopeptides
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE2 protein, human
  • BACE1 protein, human