Engineered cystine knot miniproteins as potent inhibitors of human mast cell tryptase beta

J Mol Biol. 2010 Jan 8;395(1):167-75. doi: 10.1016/j.jmb.2009.10.028. Epub 2009 Oct 21.


Here we report the design, chemical and recombinant synthesis, and functional properties of a series of novel inhibitors of human mast cell tryptase beta, a protease of considerable interest as a therapeutic target for the treatment of allergic asthma and inflammatory disorders. These inhibitors are derived from a linear variant of the cyclic cystine knot miniprotein MCoTI-II, originally isolated from the seeds of Momordica cochinchinensis. A synthetic cyclic miniprotein that bears additional positive charge in the loop connecting the N- and C-termini inhibits all monomers of the tryptase beta tetramer with an overall equilibrium dissociation constant K(i) of 1 nM and thus is one of the most potent proteinaceous inhibitors of tryptase beta described to date. These cystine knot miniproteins may therefore become valuable scaffolds for the design of a new generation of tryptase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cattle
  • Cyclotides / chemistry*
  • Cyclotides / pharmacology*
  • Cystine Knot Motifs*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Engineering*
  • Recombinant Fusion Proteins / chemistry
  • Sequence Homology, Amino Acid
  • Structural Homology, Protein
  • Tryptases / antagonists & inhibitors*
  • Tryptases / chemistry


  • Cyclotides
  • McoEeTI protein
  • Recombinant Fusion Proteins
  • trypsin inhibitor MCoTI-II
  • Tryptases