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Licensed Unlicensed Requires Authentication Published by De Gruyter February 3, 2010

Identification of novel peptide inhibitors for human trypsins

  • Ping Wu , Janne Weisell , Miikka Pakkala , Mikael Peräkylä , Lei Zhu , Riitta Koistinen , Erkki Koivunen , Ulf-Håkan Stenman , Ale Närvänen and Hannu Koistinen
From the journal Biological Chemistry

Abstract

Human trypsin isoenzymes share extensive sequence similarity, but certain differences in their activity and susceptibility to inhibitors have been observed. Using phage display technology, we identified seven different peptides that bind to and inhibit the activity of trypsin-3, a minor trypsin isoform expressed in pancreas and brain. All of the peptides contain at least two of the amino acids tryptophan, alanine and arginine, whereas proline was found closer to the N-terminus in all but one peptide. All peptides contain two or more cysteines, suggesting a cyclic structure. However, we were able to make synthetic linear variants of these peptides without losing bioactivity. Alanine replacement experiments for one of the peptides suggest that the IPXXWFR motif is important for activity. By molecular modeling the same amino acids were found to interact with trypsin-3. The peptides also inhibit trypsin-1, but only weakly, if at all, trypsin-2 and -C. As trypsin is a highly active enzyme which can activate protease-activated receptors and enzymes that participate in proteolytic cascades involved in tumor invasion and metastasis, these peptides might be useful lead molecules for the development of drugs for diseases associated with increased trypsin activity.


Corresponding author

Received: 2010-08-27
Accepted: 2010-02-14
Published Online: 2010-02-03
Published in Print: 2010-02-26

©2010 by Walter de Gruyter Berlin New York

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