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Wiley, Angewandte Chemie, 51(126), p. 14395-14398, 2014

DOI: 10.1002/ange.201408082

Wiley, Angewandte Chemie International Edition, 51(53), p. 14171-14174

DOI: 10.1002/anie.201408082

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

Journal article published in 2014 by Wael E. Houssen ORCID, 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 ORCID, Marcel Jaspars
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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.