Oral Presentation 11th Australian Peptide Conference 2015

Propargyloxyproline Regio- and Stereoisomers for Click-Conjugation of Peptides: Synthesis and Application in Linear and Cyclic Peptides (#40)

Susan E Northfield 1 2 , Simon J Mountford 2 , Jerome Wielens 2 3 , Mengjie Liu 2 , Lei Zhang 4 , Herbert Herzog 4 , Nicholas D Holliday 5 , Martin J Scanlon 2 , Michael W Parker 3 6 , David K Chalmers 2 , Philip E Thompson 2
  1. Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC, Australia
  2. Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
  3. ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  4. Neuroscience Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, NSW, Australia
  5. Institute of Cell Signalling, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom
  6. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia

The use of the click reaction for the introduction of conjugate groups, such as affinity or fluorescent labels, to a peptide for the study of peptide biochemistry and pharmacology is widespread. However, the nature and location of substituted 1,2,3-triazoles in peptide sequences may markedly affect conformation or binding as compared with native sequences. We have examined the preparation and application of propargyloxyproline (Pop) residues as a precursor to such peptide conjugates. Pop residues are available in a range of regio- and stereoisomers from hydroxyproline precursors and are readily prepared in Fmoc-protected form. They can be incorporated routinely in peptide synthesis, and broadly retain the conformational properties of the parent proline containing peptides.

We report here on the synthesis of a range of Fmoc-protected Pop regio- and stereoisomers and their incorporation into two classes of peptide of interest in our laboratories. The first were derivatives of the Y1 receptor antagonist peptide, BVD15, and the second were cyclic hexapeptides incorporating a Lys–Ile–Asp–Asn pharmacophore motif of lens epithelium-derived growth factor (LEDGF), a key protein for the activity of HIV integrase. This approach to labelling is exemplified by the preparation of biotin- and fluorophore-labelled peptides derived from linear and cyclic peptides.


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  2. SE Northfield, SJ Mountford, J Wielens, M Liu, L Zhang, H Herzog, ND Holliday, MJ Scanoln, MW Parker, DK Chalmers, PE Thompson. Propargyloxproline regio- and stereoisomers for click-conjugation of peptides. Aus J Chem, 2015, Accepted May 15, 2015
  3. AK Pandey, D Naduthambi, KM Thomas, NJ Zondlo. Proline editing: A general and practical approach to the synthesis of functionally and structurally diverse peptides. Analysis of steric versus stereoelectronic effects of 4-substituted prolines on conformation within peptides. J Am Chem Soc. 2013, 135, 4333.