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

Expanding the application and scope of arylglycines in peptides (#33)

Julien Tailhades 1 , Edward Marschall 1 , Yongwei Zhao 1 , Yee Ting Candace Ho 1 , Max Cryle 1
  1. Monash University, Clayton, VIC, Australia

Non-ribosomal peptides (NRPs) are a great source of valuable therapeutics with predominantly antifungal and antibacterial properties. It is also a valuable source of inspiration for amino acid building blocks since the non-ribosomal peptide synthetase (NRPS) machinery can function with a broad range of non-natural amino acids; giving opportunities to create diversity beyond the 20 natural amino acids.1 Amongst those biosynthetic amino acids, the arylglycine family - phenylglycine (Phg), 4-hydroxyphenylglycine (Hpg) and 3,5-dihydroxyphenylglycine (Dpg) - is rarely used in peptide chemistry due to their sensitivity to epimerisation during the solid phase peptide synthesis (SPPS) manufacturing process. Nevertheless, it remains often used in solution phase; particularly, in small molecules, short peptides or in the total synthesis of natural products. Additionally, the meta-diphenol side chain of Dpg is an excellent target for selective modifications using a Mannich reaction (applied to telavancin) or selenopeptides.2,3 Altogether, the advantages in using arylglycines in peptide synthesis are numerous and for now, limited by fundamental synthetic issues.

The optimization of SPPS was initially thought to unravel the potential of chemistry and enzymes to prepare vancomycin and teicoplanin analogues in vitro.4 The outstanding results created a unique opportunity to expand the application and the scope of arylglycines: new amino acid preparations, direct total synthesis of other NRPs, incorporation in bioactive peptides or compatibility with numerous enzymatic systems.

  1. Al Toma, R.S., Brieke, C., Cryle, M.J. & Süssmuth, R.D. Structural aspects of phenylglycines, their biosynthesis and occurrence in peptide natural products. Natural Product Reports 32, 1207-1235 (2015).
  2. Cohen, D.T. et al. A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins. Nature Chemistry 11, 78-85 (2019).
  3. Marschall, E., Cryle, M.J. & Tailhades, J. Biological, chemical, and biochemical strategies for modifying glycopeptide antibiotics. Journal of Biological Chemistry 294, 18769-18783 (2019).
  4. Tailhades, J. et al. A Chemoenzymatic Approach to the Synthesis of Glycopeptide Antibiotic Analogues. Angewandte Chemie International Edition 59, 10899-10903 (2020).