Poster Presentation 5th Modern Solid Phase Peptide Synthesis Symposium 2015

Incorporation of cystathionine as a cystine mimetic in insulin to develop more stable analogues (#53)

John A. Karas 1 2 3 4 , Nitin A. Patil 1 2 , Julien Tailhades 2 , Marc-Antoine Sani 1 4 , Denis B. Scanlon 5 , Briony E. Forbes 6 , James Gardiner 3 , Frances Separovic 1 , John D. Wade 2 , M. Akhter Hossain 2
  1. School of Chemistry, University of Melbourne, Parkville, Victoria, Australia
  2. Florey Neurosciences, The University Of Melbourne, VIC, Australia
  3. Materials Science & Engineering, CSIRO, Clayton, Victoria, Australia
  4. Bio21 Institute, University of Melbourne, Parkville, Victoria, Australia
  5. School of Chemistry, University of Adelaide, Adelaide, South Australia, Australia
  6. School of Medicine, Flinders University, Adelaide, South Australia, Australia
Basal-bolus insulin therapy is critical for maintaining tight glycemic control in patients with diabetes mellitus, especially for type 1. It is expected that worldwide, there will be 592 million people with some form of the disease by 2035, and about 80% of cases are expected to occur in developing countries.1 Therefore it is essential that these patients are treated adequately in order to avoid a humanitarian crisis. There have been many recent advances in the development of insulin-based therapeutics. But there are still issues with long-term thermal stability, particularly for short-acting analogues that mimic prandial levels of the endogenous hormone. Compromised formulations can lead to deleterious health outcomes for patients in poorer tropical regions, where refrigeration is not ubiquitous and the electricity supply can be unreliable.2 Hence there is a need to develop new analogues that are more thermally stable. One of the degradation products is caused by disulfide shuffling, leading to covalently bonded oligomers.3 In order to block this side reaction, a non-reducible cystine isostere can be incorporated in to the structure to replace each of the three existing disulfide bonds. Therefore this presentation will report on a robust synthesis and characterization of an insulin analogue with a cystathionine bridge, in order to develop a heat-stable therapeutic.
  1. IDF Diabetes Atlas, Sixth Edition. International Diabetes Federation, 2014.
  2. Weiss, M. A., Journal of Health Specialties, 1(2), 59-70, 2013.
  3. Brange, J., Havelund, S., Hougaard, P., Pharmaceutical Research, 9(6), 727-734, 1992.