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




Cyclisation Increases the Stability of the Sea Anemone Peptide APETx2 but Decreases Its Activity at Acid-Sensing Ion Channel 3 - Download this document for free, or read online. Document in PDF available to download.

The University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD 4072, Australia





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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. View Full-Text

Keywords: sea anemone; peptide; APETx2; ASIC3; cyclisation; truncation; stability sea anemone; peptide; APETx2; ASIC3; cyclisation; truncation; stability





Author: Jonas E. Jensen, Mehdi Mobli, Andreas Brust, Paul F. Alewood, Glenn F. King * and Lachlan D. Rash *

Source: http://mdpi.com/



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