3 years ago

Intramolecular cyclization of the antimicrobial peptide Polybia-MPI with triazole stapling: influence on stability and bioactivity

Intramolecular cyclization of the antimicrobial peptide Polybia-MPI with triazole stapling: influence on stability and bioactivity
Beijun Liu, Hui Liu, Zhibin Yang, Rui Wang, Haifeng Huang, Jingman Ni, Sanhu Gou, Chao Zhong, Beiyin Liu, Jia Yao, Wei Zhang
Cationic antimicrobial peptides have attracted increasing attention as a novel class of antibiotics to treat infectious diseases caused by pathogenic bacteria. However, susceptibility to protease is a shortcoming in their development. Cyclization is one approach to increase the proteolytic resistance of peptides. Therefore, to improve the proteolytic resistance of Polybia-MPI, we have synthesized the MPI cyclic analogs C-MPI-1 (i-to-i+4) and C-MPI-2 (i-to-i+6) by copper(I)-catalyzed azide–alkyne cycloaddition. Compared with MPI, C-MPI-1 displayed sustained antimicrobial activity and had enhanced anti-trypsin resistance, while C-MPI-2 displayed no antimicrobial activity. The relationship between peptide structure and bioactivity was further investigated by probing the secondary structure of the peptides by circular dichroism. This showed that C-MPI-1 adopted an α-helical structure in aqueous solution and, interestingly, had increased α-helical conformation in 30 mM sodium dodecyl sulfate and 50% trifluoroethyl alcohol compared with MPI. C-MPI-2 that was not α-helical in structure, suggesting that the propensity for α-helix conformation may play an important role in cyclic peptide design. In addition, scanning electron microscopy, propidium iodide uptake, and membrane permeabilization assays indicated that MPI and the optimized analog C-MPI-1 had membrane-active action modes, indicating that the peptides would not be susceptible to conventional resistance mechanisms. Our study provides additional insight into the influence of intramolecular cyclization at various positions on peptide structure and biological activity. In conclusion, the design and synthesis of cyclic analogs via click chemistry offer a new strategy for the development of stable antimicrobial agents. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. The MPI cyclic analogs C-MPI-1 (i- to -i+4) and C-MPI-2 (i- to -i+6) were synthesized by copper(I)-catalyzed azide-alkyne cycloaddition. Cyclic analogs have different bioactivity, and especially, C-MPI-1 has enhanced anti-trypsin resistance compared with the parent peptide MPI. The mechanism of action and the secondary structure of all peptides were further investigated.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/psc.3031

You might also like
Never Miss Important Research

Researcher is an app designed by academics, for academics. Create a personalised feed in two minutes.
Choose from over 15,000 academics journals covering ten research areas then let Researcher deliver you papers tailored to your interests each day.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.