A novel bradykinin potentiating peptide isolated from Bothrops jararacussu venom using catallytically inactive oligopeptidase EP24.15

FEBS J. 2008 May;275(10):2442-54. doi: 10.1111/j.1742-4658.2008.06389.x. Epub 2008 Apr 8.

Abstract

Characterization of the peptide content of venoms has a number of potential benefits for basic research, clinical diagnosis, development of new therapeutic agents, and production of antiserum. Here, we use a substrate-capture assay that employs a catalytically inactive mutant of thimet oligopeptidase (EC 3.4.24.15; EP24.15) to identify novel bioactive peptides in Bothrops jararacussu venom. Of the peptides captured with inactive EP24.15 and identified by mass spectrometry, three were previously identified bradykinin-potentiating peptides (BPP), <ENWPHPQIPP (Xc), <EGGWPRPGPEIPP (XIIIa) and <EARPPHPPIPP (XIe) (where <E is a pyroglutamyl residue). In addition, we identified a novel BPP peptide containing additional AP amino acids in the C-terminus (<EARPPHPPIPPAP); this novel peptide was named BPP-AP. Next, dermal and muscle microcirculations were visualized using intravital microscopy to establish the roles of peptides BPP-XIe and BPP-AP in this process. After local administration of peptide BPP-XIe (0.5 microg.microL(-1)), leukocyte rolling flux and adhesion were increased by fivefold in post-capillary venules, without any increments in vasodilatation of arterioles compared to control experiments. In contrast, local administration of BPP-AP (0.5 microg.microL(-1)) potently induced vasodilatation of arterioles (nearly 100% increase compared with the vehicle saline control), with only a small increase in leukocyte rolling flux. Therefore, the novel BPP-AP described herein has pharmacological advantages compared to the BPP-XIe. The present study further suggests that inactive oligopeptidase EP24.15 is a useful tool for the isolation of bioactive peptides from crude biological samples.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Angiotensin-Converting Enzyme Inhibitors* / chemistry
  • Angiotensin-Converting Enzyme Inhibitors* / metabolism
  • Animals
  • Blood Pressure / drug effects
  • Bothrops*
  • Bradykinin / metabolism*
  • Bradykinin / pharmacology
  • Crotalid Venoms / chemistry*
  • Endopeptidases / chemistry
  • Endopeptidases / metabolism*
  • Humans
  • Male
  • Microcirculation / drug effects
  • Molecular Sequence Data
  • Molecular Weight
  • Peptides / chemistry*
  • Peptides / genetics
  • Peptides / metabolism*
  • Peptides / pharmacology
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Rats
  • Rats, Wistar
  • Sequence Alignment

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Crotalid Venoms
  • Peptides
  • Protein Precursors
  • Endopeptidases
  • Bradykinin