Poster Presentation 8th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2022

Total Chemical Synthesis of a Biologically Active Insulin Dimer (#123)

Mengjie (Oscar) Liu 1 , Barbara White 2 , Briony Forbes 3 , John Wade 1 4 5 , M. Akhter Hossain 1 4 5
  1. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
  2. Department of Medicine (Austin Health), The University of Melbourne, Parkville, Victoria, Australia
  3. Discipline of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
  4. The Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
  5. School of Chemistry, The University of Melbourne, Parkville, VIC, Australia

Exactly 100 years after its discovery, insulin still remains the primary treatment for all type 1 and 30% of type 2 diabetes. Before the discovery of insulin in 1921, being diagnosed with diabetes was a death sentence. Since then, this first true miracle drug has saved millions of lives. However, diabetes is rapidly becoming the biggest epidemic of the 21st century, and thus more patients than ever are now dependent upon insulin therapy. According to a recent report published in Lancet Diabetes Endocrinol 2019, if no action is taken, approximately 40 million patients are predicted to be left without insulin by 2030. Therefore we need new insulin therapies that are more efficacious, safer, and convenient and which meet the demand of supply. 

We report the first total chemical synthesis of a biologically active disulfide dimeric insulin analogue, which is produced in quantitative yield from a monomeric “thiol insulin” scaffold. We characterized this analogue both in vitro and in vivo without further purification. This novel insulin dimer analogue is long-acting, highly structured, and stable in serum. Our insulin dimer exhibits insulin-like binding affinity for IGF-1 receptor and thus likely to be safer than the long-acting insulin glargine, which has 6-8 times higher affinity for IGF-1 receptor compared with insulin. We envisage that the thiol insulin scaffold can be expressed by recombinant methods, and thus our long-acting dimeric insulin can be produced on an industrial scale by incubating the thiol insulin scaffold in water followed by lyophilization (and no purification will be required as the yield is quantitative).