A defined α-helix in the bifunctional O-glycosylated natriuretic peptide TcNPa from the venom of tropidechis carinatus

Timothy Reeks, Alun Jones, Andreas Brust, Sindhuja Sridharan, Leo Corcilius, Brendan L. Wilkinson, Morten Thaysen-Andersen, Richard J. Payne, R. Manjunatha Kini, Norelle L. Daly, Paul F. Alewood

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Natriuretic peptides (NP) play important roles in human cardiac physiology through their guanylyl cyclase receptors NPR-A and NPR-B. Described herein is a bifunctional O-glycosylated natriuretic peptide, TcNPa, from Tropidechis carinatus venom and it unusually targets both NPR-A and NPR-B. Characterization using specific glycosidases and ETD-MS identified the glycan as galactosyl-β(1-3)-N-acetylgalactosamine (Gal-GalNAc) and was α-linked to the C-terminal threonine residue. TcNPa contains the characteristic NP 17-membered disulfide ring with conserved phenylalanine and arginine residues. Both glycosylated and nonglycosylated forms were synthesized by Fmoc solid-phase peptide synthesis and NMR analysis identified an α-helix within the disulfide ring containing the putative pharmacophore for NPR-A. Surprisingly, both forms activated NPR-A and NPR-B and were relatively resistant towards proteolytic degradation in plasma. This work will underpin the future development of bifunctional NP peptide mimetics.

Original languageEnglish
Pages (from-to)4828-4831
Number of pages4
JournalAngewandte Chemie - International Edition
Volume54
Issue number16
DOIs
Publication statusPublished - 13 Apr 2015

Keywords

  • Tropidechis carinatus
  • glycopeptide synthesis
  • helical structures
  • natriuretic peptide TcNPa
  • snake toxin

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