Oral Presentation 5th Modern Solid Phase Peptide Synthesis Symposium 2015

Fmoc-based solid phase synthesis strategies to access biosynthetic intermediates of glycopeptide antibiotics that enable enzymatic bioconjugation (#22)

Max J. Cryle 1
  1. Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Heidelberg, Baden-Wuerttemberg, Germany

Non-ribosomal peptide synthesis is a fascinating way in which nature assembles peptides in a stepwise manner without the involvement of the ribosome. This enzymatic assembly line produces many important natural products and these often contain a diverse range of amino acids not found in proteins: important examples are arylglycines, which are found in a range of antibiotic compounds that includes the glycopeptide antibiotics. In order to characterise and understand the biosynthesis of such natural products we need to be able to access peptides intermediates: additionally, these must also be modified in such a way as to allow ligation to the biosynthetic machinery itself, as non-ribosomal peptide synthesis relies on the tethering of intermediates as thioesters to carrier protein domains. To address this need, we have developed a rapid route to glycopeptide precursor CoA conjugates based on Fmoc-chemistry that affords both high yields and excellent purities. This route allows the synthesis of peptide CoA-conjugates containing racemization-prone arylglycine residues: such residues have previously been inaccessible to peptide synthesis using Fmoc-type chemistry. We are also investigating other methods of synthesising peptides in a form appropriate for loading onto carrier proteins, and recent results of these investigations will be presented here.

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  2. 4. A facile Fmoc solid phase synthesis strategy to access epimerization-prone biosynthetic intermediates of glycopeptide antibiotics. Brieke C, Cryle MJ. Org Lett. 2014 May 2;16(9):2454-7. doi: 10.1021/ol500840f
  3. 2. Rapid access to glycopeptide antibiotic precursor peptides coupled with cytochrome P450-mediated catalysis: towards a biomimetic synthesis of glycopeptide antibiotics. Brieke C, Kratzig V, Haslinger K, Winkler A, Cryle MJ. Org Biomol Chem. 2015 Feb 21;13(7):2012-21. doi: 10.1039/c4ob02452d.
  4. 4. Structural aspects of phenylglycines, their biosynthesis and occurrence in peptide natural products. Al Toma RS, Brieke C, Cryle MJ, Süssmuth RD. Nat Prod Rep. 2015 Jul 22;32(8):1207-35. doi: 10.1039/c5np00025d.