Oral Presentation 13th Australian Peptide Conference 2019

Design and Synthesis of 13-membered Cyclic Tetrapeptides as Novel Antimicrobials with Enhanced Therapeutic Window  (#51)

Vijayalekshmi Sarojini 1 , Alan Cameron 1 , Kyriakos Varnava 1 , Patrick Edwards 2 , Elena Harjes 2 , Christopher Squire 1
  1. The University of Auckland, Auckland, New Zealand
  2. Massey University, Palmerston North, New Zealand

Naturally occurring β-turns are important in mediating protein folding, receptor binding interactions as well as in serving as sites for post-translational modification in proteins.1-3 Therefore, the development of novel β-turn mimetics is of fundamental interest as well as aid in providing novel frameworks for drug design. Non-protein amino acids bearing N-methylation, α,α-dialkylation or D-configurations have been found to induce b-turns and stabilize b-hairpin conformations in synthetic peptides.4-6 Despite these literature efforts, the realization of designed β-hairpin peptides with biological activities and the use of novel b-turns to facilitate the syntheses of cyclic tetrapeptides remains relatively less documented and present several challenges. Our recent research developed a novel β-turn scaffold, that permits the pre-organization of designed linear tetrapeptides and facilitate their cyclization to yield synthetically challenging cyclic tetrapeptides (CTPs) in quantitative yields.7 Parameters such as solvent polarity and ring dissection were investigated during the syntheses of the CTPs resulting in optimized synthetic strategies with significant improvements to product yields than previously reported.7,8 The designed β-turn was also incorporated in analogues of naturally occurring β-hairpin antimicrobials and de novo designed peptides resulting in synthetic analogues with altered molecular architecture and providing broad-spectrum β-hairpin antimicrobial peptides with enhanced therapeutic window.9 Further investigations have now allowed us to fine-tune the amino acid sequences for engineering acyclic and cyclic antimicrobial peptides that adopt β-hairpin structures. A summary of these findings that include chemical syntheses, structural analyses and bioactivity studies will be presented. 

  1. Brahmachari, S. K.; Ananthanarayanan, V. S. Beta-turns in nascent procollagen are sites of posttranslational enzymatic hydroxylation of proline. Proc Natl Acad Sci U S A 1979, 76 (10), 5119-23
  2. Chou, P. Y.; Fasman, G. D. Beta-turns in proteins. J Mol Biol 1977, 115 (2), 135-75.
  3. Chatterjee, J.; Gilon, C.; Hoffman, A.; Kessler, H. N-Methylation of Peptides: A New Perspective in Medicinal Chemistry. Accounts Chem Res 2008, 41 (10), 1331-42.
  4. Chatterjee, J.; Gilon, C.; Hoffman, A.; Kessler, H. N-Methylation of Peptides: A New Perspective in Medicinal Chemistry. Accounts Chem Res 2008, 41 (10), 1331-42.
  5. Karle, I. L.; Awasthi, S. K.; Balaram, P. A designed beta-hairpin peptide in crystals. P Natl Acad Sci USA 1996, 93 (16), 8189-93.
  6. Imperiali, B.; Fisher, S. L.; Moats, R. A.; Prins, T. J. A Conformational Study of Peptides with the General Structure Ac-L-Xaa-Pro-D-Xaa-L-Xaa-Nh2 - Spectroscopic Evidence for a Peptide with Significant Beta-Turn Character in Water and in Dimethyl-Sulfoxide. J Am Chem Soc 1992, 114 (9), 3182-8.
  7. Cameron, A. J.; Squire, C. J.; Edwards, P. J. B.; Harjes, E.; Sarojini, V. Crystal and NMR Structures of a Peptidomimetic beta-Turn That Provides Facile Synthesis of 13-Membered Cyclic Tetrapeptides. Chem Asian J 2017, 12 (24), 3195-202.
  8. Xin, D. Y.; Burgess, K. Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility. Organic & Biomolecular Chemistry 2016, 14 (22), 5049-58.
  9. Cameron, A. J.; Edwards, P. J. B.; Harjes, E.; Sarojini, V. Tyrocidine A Analogues Bearing the Planar d-Phe-2-Abz Turn Motif: How Conformation Impacts Bioactivity. J Med Chem 2017, 60 (23), 9565-74.