Imidazolium-based warheads strongly influence activity of water-soluble peptidic transglutaminase inhibitors

Eur J Med Chem. 2013 Aug:66:526-30. doi: 10.1016/j.ejmech.2013.05.018. Epub 2013 Jun 7.

Abstract

New peptidic water-soluble inhibitors are reported. In addition to the carboxylate moiety, a new polar warhead was explored. Depending on the size of its substituents, the newly appended imidazolium scaffold designed to enhance the hydrophilic character of the inhibitors could induce a good inhibition for tissue transglutaminase (TG2) and blood coagulation factor XIIIa (FXIIIa). Correlated with the narrow tunnel that hosts the target catalytic cysteine residue, the various modulations suggest a bent conformation of the ligands as the binding pattern mode. Analogues in the dialkylsulfonium series were also tested and showed specificity for TG2 over FXIIIa.

Keywords: Coagulation factor XIIIa (FXIIIa); Dialkylsulfonium; Imidazolium warheads; Peptidic inhibitors; Tissue transglutaminase (TG2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • GTP-Binding Proteins
  • Humans
  • Imidazoles / chemistry*
  • Models, Molecular
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Protein Conformation
  • Protein Glutamine gamma Glutamyltransferase 2
  • Solubility
  • Transglutaminases / antagonists & inhibitors*
  • Transglutaminases / chemistry
  • Water / chemistry*

Substances

  • Enzyme Inhibitors
  • Imidazoles
  • Peptides
  • Water
  • imidazole
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins