A Total New Game for the Synthesis of Disulfide-Containing Peptides

F. Albericio, M. Góngora-Benítez, T. Postma, L. Mendive, I. Ramos-Tomillero, A. C. Breman, M. Giraud, A. Basso, T. Bruckdorfer, M. Royo, J. Tulla-Puche

J. Pept. Sci. 2012; 18: 29; https://doi.org/10.1002/psc.2448

Abstract: The overall goal of our research is to capitalize on peptides of natural origin and their biological activity and chemistry. Peptide discovery from plants and animals, development of synthesis and folding methods, and structural and biological characterization of those peptides are central themes for the group. In particular, our focus has been on the family of cyclic and cystine knotted plant proteins known as cyclotides(1,2). This peptide family defines an ultra-stable peptide scaffold that may be considered ideal for peptide engineering. Currently, we are exploring the antimicrobial activity of cyclotides and their mechanism of action. We have recently shown that specific cyclotides have potent effect against gram-negative bacteria(3), and that they act by membrane thinning(4). However, recent results demonstrate that the membrane is not the only target of these peptides. At sub-cytotoxic concentrations, cyclotides demonstrate a different mode of action: they cross over the membrane and they induce DNA-damage. To explore the chemical diversity of cyclotide bearing plants, a large number of plants and peptides have been characterized over the years. Because of their stability, cyclotides are ideal targets for the peptidomic-like approach that we use for discovery, and indeed we have successfully identified intact cyclotides in herbaria collections nearly 200 years old. However, using the same approach we have also recently discovered, non-cyclic but cystine-knotted, novel antimicrobial peptides.