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Mar. Drugs 2012, 10(7), 1511-1527; doi:10.3390/md10071511
Article

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

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Received: 30 May 2012 / Revised: 14 June 2012 / Accepted: 6 July 2012 / Published: 16 July 2012
(This article belongs to the Special Issue Sea Anemone Toxins)
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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.
Keywords: sea anemone; peptide; APETx2; ASIC3; cyclisation; truncation; stability sea anemone; peptide; APETx2; ASIC3; cyclisation; truncation; stability
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Jensen, J.E.; Mobli, M.; Brust, A.; Alewood, P.F.; King, G.F.; Rash, L.D. Cyclisation Increases the Stability of the Sea Anemone Peptide APETx2 but Decreases Its Activity at Acid-Sensing Ion Channel 3. Mar. Drugs 2012, 10, 1511-1527.

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