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

Angewandte Chemie
Timothy ReeksPaul F Alewood

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.

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Citations

Dec 4, 2015·Journal of Proteomics·Timothy ReeksPaul F Alewood
Dec 13, 2017·The Biochemical Journal·Sindhuja Sridharan, R Manjunatha Kini
Nov 18, 2018·Toxins·Aisha MunawarChristian Betzel
Feb 15, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Sindhuja SridharanArthur Mark Richards

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