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

Marine Drugs

Jonas E. Jensen²  Mehdi Mobli²  Andreas Brust²  Paul F. Alewood²  Glenn F. King¹ 

[1] The University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD 4072, Australia;

关键词: sea anemone;    peptide;    APETx2;    ASIC3;    cyclisation;    truncation;    stability;   

DOI  :  10.3390/md10071511

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.