Potent inhibitors of beta-tryptase and human leukocyte elastase based on the MCoTI-II scaffold

J Med Chem. 2009 Oct 22;52(20):6197-200. doi: 10.1021/jm901233u.

Abstract

MCoTI-II is a member of a class of microproteins known as cyclotides that possess a macrolactam-cystine knot scaffold imparting exceptional physiological stability and structural rigidity. Modification of residues in the active loop and engineered truncations have resulted in MCoTI-II analogues that possess potent activity against two therapeutically significant serine proteases: beta-tryptase and human leukocyte elastase. These results suggest that MCoTI-II is a versatile scaffold for the development of protease inhibitors against targets in inflammatory disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cyclotides / chemistry*
  • Cyclotides / pharmacology*
  • Drug Design
  • Humans
  • Leukocyte Elastase / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Sequence Data
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • Protein Conformation
  • Substrate Specificity
  • Tryptases / antagonists & inhibitors*

Substances

  • Cyclotides
  • Protease Inhibitors
  • trypsin inhibitor MCoTI-II
  • Leukocyte Elastase
  • Tryptases