Poster Presentation 10th Australian Peptide Conference 2013

Cyclization of the antimicrobial peptide gomesin with native chemical ligation: Influences on stability and bioactivity (#114)

Lai Yue Chan 1 , Veronica M. Zhang 2 , Yen-hua Huang 1 , Norman C. Waters 2 , Paramjit S. Bansal 3 , David J. Craik 1 , Norelle L. Daly 3
  1. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  2. Australian Army Malaria Institute , and The University of Queensland, Brisbane, Queensland, Australia
  3. Queensland Tropical Health Alliance, School of Pharmacy and Molecular Sciences and Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University, Cairns, Queensland, Australia

Gomesin is an antimicrobial peptide which contains two disulfide bonds (CysI-CysIV and CysII-CysIII) in a beta-hairpin structure.1 Poor stability often hinders potential peptides such as gomesin for further development into drug candidates. There are many ways to improve peptide stability, one possible way is through backbone cyclization. An example on using this approach is a study based on a small bioactive peptide, Vc1.1, which derived from the cone snail venom.2 Improvement on stability and bioactivity were observed after cyclization of Vc1.1. Given the close proximity of the N and C termini of gomesin, cyclization approach was utilized in this study to assess if similar improvements could be observed. Cyclization was done by substituting the pyro-glutamic acid residue in the sequence with a glycine residue as a linker and using native chemical ligation3 method to link both N and C termini. A range of in vitro assays including membrane binding study were carried out to compare the bioactivity of the linear and cyclic forms of gomesin. Structural studies by NMR were also carried out to characterize the cyclic form of gomesin. In summary, this study has provided additional insights into the range of improvements in bioactivity and stability that can be achieved as a result of backbone cyclization of peptides.

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  3. P. E. Dawson, T. W. Muir, I. Clark-Lewis, S. B. Kent, Science 1994, 266, 776-779.