Poster Presentation 8th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2022

Synthetic strategies towards the total synthesis of sactipeptide natural products. (#128)

Karen Milewska 1 , Lara Malins 1
  1. Australian National University, Acton, ACT, Australia

Sactipeptides are an important class of ribosomally synthesised post-transitionally modified peptides (RiPPs). The biosynthesis of sactipeptides involves the S-adenosyl methionine (SAM) super family of enzymes which play a crucial role in the post-translational formation of a thioether bridge between the sulfur of cysteine and the α-carbon of an opposing amino acid1. This sactionine linkage is a distinctive feature of the members of this family2 and multiple new examples have been discovered in recent years3, 4. The intriguing structural features of this family result in a constrained macrocyclic topology contributing to their antimicrobial activity (in particular against Clostridia)5 as well as their structural integrity, making these natural products interesting targets for antibiotic development.

This presentation will focus on synthetic strategies undertaken towards the synthesis of subtilosin A and SKF. The key challenge posed by these fascinating peptide natural products is the unique thioether linkage. As chemical approaches for this cross-link are largely unexplored, strategies for the synthesis of this structural motif via building block approaches as well as late-stage modification strategies will be the main focus of this presentation.

References:

  1. T. Jarret, J. Biol. Chem. 2015, 290, 3972–3979.
  2. Fluhe, M. A. Marahiel, Curr. Opin. Chem. Biol. 2013, 17, 605–612.
  3. Balty, A. Guillot, L. Fradale, C. Brewee, M. Boulay, X. Kubiak, A. Benjdia, O. Berteau, J. Biol. Chem. 2019, 294, 14512–14525.
  4. B. Bushin, B. C. Covington, B. E. Rued, M. J. Federle, M. R. Seyedsayamdost, J. Am. Chem. Soc. 2020, 142, 16265–16275.
  5. C. Rea, C. S. Sit, E. Clayton, P. M. O’Connor, R. M. Whittal, J. Zheng, J. C. Vederas, R. P. Ross, C. Hill, Proc. Natl. Acad. Sci. USA. 2010, 107, 9352­–9357.