Abstract

Cyclic peptides are an exciting and underexplored group of compounds with unique biological properties. They are preferred to linear variants as they can cross cell membranes and are more stable to metabolic enzymes. There is currently a pressing need especially within the pharmaceutical sector for testing compound libraries based on these scaffolds which share with biologics the ability to modulate the challenging protein-protein interactions and are much cheaper and can be orally administered. Novel cyclic peptides can be designed in silico that could have promising therapeutic properties but currently have no method of manufacture. Therefore, efficient and low-cost catalytic methods to produce them are in demand. Cyanobactins are complex cyclic peptides containing heterocycles, D-stereocentres and prenylated residues produced by the action of post-translation modifying enzymes on a precursor peptide (Figure 1). We have structurally defined all the main enzymes involved in their production – the heterocyclase, azoline oxidase, protease, macrocyclase and prenylase, and have generated systems to produce complex cyclic peptides using these enzymes1,2,3. The more efficient system relies on the use of engineered enzymes that can act on simplified synthetic substrates3 and generate molecules containing multiple non-amino acid moieties4. This chemoenzymatic approach is being commercialised to generate complex cyclic peptides that can be used to treat complex diseases mediated by protein-protein interactions, such as immune disorders.

Figure 1. The enzymes involved in formation of the patellamides. 1. “An Efficient Method for the In Vitro Production of Azoline-Based Cyclic Peptides.” Wael E. Houssen, Andrew F. Bent, Andrew R. McEwan, Nathalie Pieiller, Jioji Tabudravu, Jesko Koehnke, Greg Mann, Rosemary I. Adaba, Louise Thomas, Usama W. Hawas, Huanting Liu, Ulrich Schwarz-Linek, Margaret C. M. Smith, James H. Naismith, Marcel Jaspars, Angew. Chem.-Int. Ed. 2014 53 14171 2. “Structural Analysis of Leader Peptide Binding Enables Leader-Free Cyanobactin Processing” Jesko Koehnke, Greg Mann, Andrew F Bent, Hannes Ludewig, Sally Shirran, Catherine Botting, Tomas Lebl, Wael E Houssen, Marcel Jaspars, & James H Naismith Nat Chem Biol 2015, 11, 558 3. “Synthesis of hybrid cyclopeptides through enzymatic macrocyclisation” Emilia Oueis, Bruno Nardone, Marcel Jaspars, Nicholas J. Westwood and James H. Naismith, ChemistryOpen 2017, 6, 11-14