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

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 famil...

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Bibliographic Details
Published in:Angewandte Chemie (International ed.) 2014-12, Vol.53 (51), p.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: Article
Language:English
Subjects:
Amino acids
Azoles - chemistry
Azoles - metabolism
Biomedical materials
biosynthesis
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
ribosomal peptides
Scaffolds
Synthesis
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Summary: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.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201408082