An efficient method for the in vitro production of Azol(in)e-based cyclic peptides
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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.
Houssen , W E , Bent , A F , McEwan , A R , Pieiller , N , Tabudravu , J , Koehnke , J , Mann , G , Adaba , R I , Thomas , L , Hawas , U W , Liu , H , Schwarz-Linek , U , Smith , M C M , Naismith , J H & Jaspars , M 2014 , ' An efficient method for the in vitro production of Azol(in)e-based cyclic peptides ' Angewandte Chemie International Edition , vol. 53 , no. 51 , pp. 14171-14174 . DOI: 10.1002/anie.201408082
Angewandte Chemie International Edition
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited (http://creativecommons.org/licenses/by/4.0/)
DescriptionThis paper was funded by: Funded Access, Leverhulme Trust. Grant Number: RPG-2012-504, TSB. Grant Number: 131181, ERC. Grant Number: 339367, and BBSRC. Grant Number: BB/K015508/1
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