Oral Presentation 9th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2023

Semisynthesis of Novel Insulin Analogues (93082)

Claire M Weekley 1 , Rong Xu 2 , Michael W Parker 1 , Christoph E Hagemeyer 2 , John A Karas 3
  1. Bio21 Institute, University of Melbourne, Parkville, Victoria, Australia
  2. Australian Centre for Blood Diseases (ACBD), Monash University, Melbourne, Victoria, Australia
  3. School of Chemistry, University of Melbourne, Parkville, Victoria, Australia

Insulin replacement therapy is essential for the effective management of type 1 diabetes. However, despite the relative success of subcutaneously administered basal/bolus insulin dosage regimens in controlling glycaemic levels, significant challenges remain to optimise the effective treatment of diabetes worldwide, such as increasing therapeutic compliance, and enhancing overall quality of life.1

To address these issues, my research primarily seeks to develop insulin analogues with improved physico-chemical and in vivo stability, for oral delivery. To achieve this, one strategy that we are adopting is to replace the existing disulfide bonds in insulin with lactam or thioether bridges.2 Cystine mimetics such as these are more resistant to reduction in vivo and thermal degradation. A key feature of our research is the development of scalable semisynthetic methods to incorporate the non-natural cystine mimetics,3 which will be essential for the viability of the new insulin variants as drug leads.

  1. 1. Zaykov, A. N. et al., Pursuit of a perfect insulin (2016). Nature Reviews Drug Discovery, 15, 425–439.
  2. 2. Karas, J. A. et al., Total Chemical Synthesis of an Intra-A-Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability (2016). Angewandte Chemie - International Edition, 55, 47, 14743-14747.
  3. 3. Karas, J. A. et al., The Chemical Synthesis of Insulin: An Enduring Challenge (2021). Chemical Reviews, 121, 8, 4531-4560.