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 . https://doi.org/10.1002/anie.201408082
Angewandte Chemie International Edition
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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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