An Efficient Method for the In Vitro Production of Azol(in)e-Based Cyclic Peptides

• Published in: Angewandte Chemie International Edition Vol. 53; no. 51; pp. 14171 - 14174
• Main Authors: Houssen, Wael E., Bent, Andrew F., McEwan, Andrew R., Pieiller, Nathalie, Tabudravu, Jioji, Koehnke, Jesko, Mann, Greg, Adaba, Rosemary I., Thomas, Louise, Hawas, Usama W., Liu, Huanting, Schwarz-Linek, Ulrich, Smith, Margaret C. M., Naismith, James H., Jaspars, Marcel
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 15.12.2014; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Amino acids; Azoles - chemistry; Azoles - metabolism; Biomedical materials; biosynthesis; Chemistry; Chemistry, Multidisciplinary; Communications; cyanobactins; cyclic peptides; Enzymes; Heterocyclic compounds; Molecular Conformation; Oxidase; Oxidoreductases - chemistry; Oxidoreductases - metabolism; patellamides; Peptide Hydrolases - chemistry; Peptide Hydrolases - metabolism; Peptides; Peptides, Cyclic - biosynthesis; Peptides, Cyclic - chemistry; Pharmaceuticals; Phosphorus-Oxygen Lyases - chemistry; Phosphorus-Oxygen Lyases - metabolism; Physical Sciences; ribosomal peptides; Scaffolds; Science & Technology; Synthesis; cyclic peptides; ROUTE; ribosomal peptides; biosynthesis; cyanobactins; patellamides; DISCOVERY; MACROCYCLIZATION
• DOI: 10.1002/anie.201408082
• ISSN: 1433-7851

Heterocycle‐containing cyclic peptides are promising scaffolds for the pharmaceutical industry but their chemical synthesis is very challenging. A new universal method has been devised to prepare these compounds by using a set of engineered marine‐derived enzymes and substrates obtained from a family of ribosomally produced and post‐translationally modified peptides called the cyanobactins. The substrate precursor peptide is engineered to have a non‐native protease cleavage site that can be rapidly cleaved. The other enzymes used are heterocyclases that convert Cys or Cys/Ser/Thr into their corresponding azolines. A macrocycle is formed using a macrocyclase enzyme, followed by oxidation of the azolines to azoles with a specific oxidase. The work is exemplified by the production of 17 macrocycles containing 6–9 residues representing 11 out of the 20 canonical amino acids. Heterocycle‐containing cyclic peptides are promising scaffolds for the pharmaceutical industry, but their chemical synthesis is very challenging. A new universal method has been devised to prepare these compounds by using a set of engineered marine‐derived enzymes and substrates.