Oral Presentation 14th Australian Peptide Conference 2022

Controlling cyclic peptide conformation using stereoselective fluorination chemistry (#4)

Luke Hunter 1
  1. School of Chemistry, The University of New South Wales (UNSW), Sydney, NSW, Australia

Cyclic peptides are promising lead structures for drug development. Cyclic peptides are usually superior to linear peptides in terms of their resistance to metabolism, their capacity for crossing cell membranes, and the potency and selectivity of their target-binding interactions. However, when attempting to progress a cyclic peptide lead compound towards therapeutic applications, it is frequently necessary to “fine-tune” the molecular conformation (i.e. to subtly modify the global shape of the macrocycle, and/or to alter the internal hydrogen bonding pattern).[1]

My research group focuses on novel strategy for fine-tuning the conformations of cyclic peptides: our approach is to incorporate a stereoselectively-fluorinated amino acid within the macrocycle. The presence of fluorine within an organic molecule impacts upon the molecular geometry in predictable ways, because the highly polarised C-F bond tends to engage in a variety of intramolecular dipolar and hyperconjugative interactions which stabilise certain rotamers over others. This capacity for conformational control provides a means to optimise the shapes, and hence the functions, of medicinally relevant cyclic peptides.

In this presentation, I will outline how my research group has applied this strategy to modify the functions of several cyclic peptides including an anion-binding cyclic heptapeptide;[2,3] a heat shock protein-binding cyclic pentapeptide; and an integrin-binding cyclic tetrapeptide.[4]

  1. Jwad R., Weissberger D., Hunter L., Strategies for fine-tuning the conformations of cyclic peptides, Chem. Rev. 2020, 120, 9743.
  2. Hu X.G., Thomas D.R., Griffith R., Hunter L., Stereoselective fluorination alters the geometry of a cyclic peptide: exploration of backbone‐fluorinated analogues of unguisin A, Angew. Chem. Int. Ed. 2014, 53, 6176.
  3. Ariawan A.D., Webb J.E.A., Howe E.N.W., Gale P.A., Thordarson P., Hunter L., Cyclic peptide unguisin A is an anion receptor with high affinity for phosphate and pyrophosphate, Org. Biomol. Chem. 2017, 15, 2962.
  4. Au C., Gonzalez C., Leung Y.C., Mansour F., Trinh J., Wang Z., Hu X.-G., Griffith R., Pasquier E., Hunter L., Tuning the properties of a cyclic RGD-containing tetrapeptide through backbone fluorination, Org. Biomol. Chem. 2019, 17, 664.