Substrate specificity and inhibitory study of human airway trypsin-like protease

Bioorg Med Chem. 2010 Aug 1;18(15):5504-9. doi: 10.1016/j.bmc.2010.06.059. Epub 2010 Jun 22.

Abstract

Human airway trypsin-like protease (HAT), also referred to as TMPRSS11D, is an important physiological enzyme with the main activity pronounced in an airway. In this work we have described the substrate specificity and selectivity study of the protease, performed by the combinatorial approach. Fluorogenic/chromogenic tetrapeptide library was used for this purpose. The most efficiently hydrolyzed substrates' sequences that we selected were ABZ-Arg-Gln-Asp-Arg(Lys)-ANB-NH(2). The most active inhibitor with C-terminal Arg residue underwent detectable proteolysis action in the presence of 35pM of HAT. Based on the selected sequences the two peptide aldehydes were synthesized and (Abz-Arg-Gln-Asp-Arg(Lys)-H) were found to be an effective HAT inhibitor, working in nanomolar range with inhibition constant 54nM and 112nM, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Combinatorial Chemistry Techniques
  • Fluorescence Resonance Energy Transfer
  • Fluorescent Dyes / chemistry
  • Humans
  • Kinetics
  • Peptide Library
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Peptides / pharmacology
  • Serine Endopeptidases / chemistry*
  • Serine Endopeptidases / metabolism
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / pharmacology
  • Substrate Specificity

Substances

  • Fluorescent Dyes
  • Peptide Library
  • Peptides
  • Serine Proteinase Inhibitors
  • Serine Endopeptidases
  • human airway trypsin-like protease