Back to Search Start Over

Cyclisation Increases the Stability of the Sea Anemone Peptide APETx2 but Decreases Its Activity at Acid-Sensing Ion Channel 3

Authors :
Lachlan D. Rash
Glenn F. King
Paul F. Alewood
Mehdi Mobli
Andreas Brust
Jonas E. Jensen
Source :
Marine Drugs, Vol 10, Iss 7, Pp 1511-1527 (2012)
Publication Year :
2012
Publisher :
MDPI AG, 2012.

Abstract

APETx2 is a peptide isolated from the sea anemone Anthopleura elegantissima. It is the most potent and selective inhibitor of acid-sensing ion channel 3 (ASIC3) and it is currently in preclinical studies as a novel analgesic for the treatment of chronic inflammatory pain. As a peptide it faces many challenges in the drug development process, including the potential lack of stability often associated with therapeutic peptides. In this study we determined the susceptibility of wild-type APETx2 to trypsin and pepsin and tested the applicability of backbone cyclisation as a strategy to improve its resistance to enzymatic degradation. Cyclisation with either a six-, seven- or eight-residue linker vastly improved the protease resistance of APETx2 but substantially decreased its potency against ASIC3. This suggests that either the N- or C-terminus of APETx2 is involved in its interaction with the channel, which we confirmed by making N- and C-terminal truncations. Truncation of either terminus, but especially the N-terminus, has detrimental effects on the ability of APETx2 to inhibit ASIC3. The current work indicates that cyclisation is unlikely to be a suitable strategy for stabilising APETx2, unless linkers can be engineered that do not interfere with binding to ASIC3.

Details

Language :
English
ISSN :
16603397
Volume :
10
Issue :
7
Database :
Directory of Open Access Journals
Journal :
Marine Drugs
Publication Type :
Academic Journal
Accession number :
edsdoj.42627fb81e9b4280b180887c15b87a5b
Document Type :
article
Full Text :
https://doi.org/10.3390/md10071511