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An Efficient Method for the In Vitro Production of Azol(in)e‐Based Cyclic Peptides |
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| Authors: | Dr Wael E Houssen Andrew F Bent Dr Andrew R McEwan Nathalie Pieiller Dr Jioji Tabudravu Dr Jesko Koehnke Greg Mann Rosemary I Adaba Dr Louise Thomas Dr Usama W Hawas Dr Huanting Liu Dr Ulrich Schwarz‐Linek Prof Margaret C M Smith Prof James H Naismith Prof Marcel Jaspars |
| Institution: | 1. Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE (UK);2. Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD (UK);3. Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516 (Egypt);4. Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST (UK);5. Marine Chemistry Department, Faculty of Marine Sciences, King Abdulaziz University, Jeddah 21589 (Saudi Arabia);6. Department of Biology, University of York, Wentworth Way, York YO10 5DD (UK) |
| 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. |
| Keywords: | cyanobactins cyclic peptides biosynthesis patellamides ribosomal peptides |