Selection of peptomeric inhibitors of bovine alpha-chymotrypsin and cathepsin G based on trypsin inhibitor SFTI-1 using a combinatorial chemistry approach

Mol Divers. 2010 Feb;14(1):51-8. doi: 10.1007/s11030-009-9142-z. Epub 2009 Apr 9.

Abstract

A peptomeric library consisting of 360 monocyclic analogues of trypsin inhibitor SFTI-1 isolated from sunflower seeds was designed and synthesized by a solid-phase approach in order to select chymotrypsin and cathepsin G inhibitors. All peptomers contained a proteinogenic-Phe-mimicking N-benzylglycine (Nphe) at positions 5 and 12. Into the synthesized library, different peptoid monomers were introduced in the 7-10 segment. Deconvolution of the library against both proteinases through an iterative method in solution revealed that the strongest chymotrypsin inhibitory activity was displayed by two analogues, [Nphe(5,12)]SFTI-1 (1) and [Nphe(5,12), Naem(8)]SFTI-1 (2), where Naem stands for N-(2-morpholinoethyl)glycine. After deconvolution against a cathepsin G analogue, [Nphe(5,12), Npip(8,9), Nnle(10)] SFTI-1 (3) (Npip = N-(3,4-methylenedioxybenzyl)glycine) appeared to be the most potent inhibitor with a high serum stability. It is worth noting that the analogues obtained by a combinatorial approach display high specificity towards one of the experimental enzymes. Another interesting feature is the lack of Pro8 in analogues 2 and 3, the amino acid residue absolutely conserved in the family of Bownan-Birk inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cathepsin G / antagonists & inhibitors*
  • Cathepsin G / genetics
  • Cattle
  • Chromatography, High Pressure Liquid
  • Chymotrypsin / antagonists & inhibitors*
  • Chymotrypsin / genetics
  • Combinatorial Chemistry Techniques / methods*
  • Computational Biology / methods
  • Glycine / chemistry
  • Humans
  • Peptide Library
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / genetics
  • Trypsin Inhibitors / chemistry*
  • Trypsin Inhibitors / genetics

Substances

  • Peptide Library
  • Peptides
  • Peptides, Cyclic
  • SFTI-1 peptide, sunflower
  • Trypsin Inhibitors
  • Chymotrypsin
  • alpha-chymotrypsin
  • Cathepsin G
  • Glycine