Engineering stable peptide toxins by means of backbone cyclization: stabilization of the α-conotoxin MII

Authors

Richard J. Clark, University of Queensland
Harald Fischer, University of Queensland
Louise Dempster, University of Queensland
Norelle L. Daly, University of Queensland
K. . Johan Rosengren, University of Queensland
Simon T. Nevin, University of Queensland
Frederic A. Meunier, University of Queensland
David J. Adams, University of QueenslandFollow
David J. Craik, University of Queensland

RIS ID

105738

Publication Details

Clark, R. J., Fischer, H., Dempster, L., Daly, N. L., Rosengren, K., Nevin, S. T., Meunier, F. A., Adams, D. J. & Craik, D. J. (2005). Engineering stable peptide toxins by means of backbone cyclization: stabilization of the α-conotoxin MII. Proceedings of the National Academy of Sciences of USA, 102 (39), 13767-13772.

Abstract

Conotoxins (CTXs), with their exquisite specificity and potency, have recently created much excitement as drug leads. However, like most peptides, their beneficial activities may potentially be undermined by susceptibility to proteolysis in vivo. By cyclizing the α-CTX MII by using a range of linkers, we have engineered peptides that preserve their full activity but have greatly improved resistance to proteolytic degradation. The cyclic MII analogue containing a seven-residue linker joining the N and C termini was as active and selective as the native peptide for native and recombinant neuronal nicotinic acetylcholine receptor subtypes present in bovine chromaffin cells and expressed in Xenopus oocytes, respectively. Furthermore, its resistance to proteolysis against a specific protease and in human plasma was significantly improved. More generally, to our knowledge, this report is the first on the cyclization of disulfide-rich toxins. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine.