Oral Presentation 6th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2017

Total chemical synthesis of an intra-A-chain cystathionine human insulin analogue with enhanced thermal stability (#17)

John A Karas 1 , Nitin A Patil 2 , Julien Tailhades 3 , Marc-Antoine Sani 4 5 , Denis Scanlon 6 , Briony Forbes 7 , James Gardiner 8 , Frances Separovic 4 5 , John Wade 2 , M. Akhter Hossain 2
  1. The University of Melbourne, The University Of Melbourne, VIC, Australia
  2. Florey Neurosciences, The University Of Melbourne, VIC, Australia
  3. Biochemistry and Molecular Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
  4. School of Chemistry, University of Melbourne, Parkville, Victoria, Australia
  5. Bio21 Institute, University of Melbourne, Parkville, Victoria, Australia
  6. School of Chemistry, University of Adelaide, Adelaide, South Australia, Australia
  7. School of Medicine, Flinders University, Adelaide, South Australia, Australia
  8. Materials Science & Engineering, CSIRO, Clayton, Victoria, Australia

Despite recent advances in the treatment of diabetes mellitus, storage of insulin formulations at 4°C is still necessary to minimize chemical degradation. This is problematic in tropical regions where reliable refrigeration is not ubiquitous. Some degradation byproducts are caused by disulfide shuffling of cystine that leads to covalently bonded oligomers. Consequently we examined the utility of the non-reducible cystine isostere, cystathionine, within the A-chain. Reported herein is an efficient method for forming this mimic using simple monomeric building blocks. The intra-A-chain cystathionine insulin analogue was obtained in good overall yield, chemically characterized and demonstrated to possess native binding affinity for the insulin receptor isoform B. It was also shown to possess significantly enhanced thermal stability indicating potential application to next-generation insulin analogues.