Developing non-fibrillating and long-acting insulin analogs to treat diabetes
Before the discovery of insulin in 1921, being diagnosed with diabetes was a death sentence. Insulin has since saved millions of lives. However, diabetes is rapidly becoming the biggest epidemic of the twenty-first century and more patients than ever are dependent upon insulin therapy. According to a recent report, if no action is taken, more than 40 million patients are predicted to be left without insulin by 2030.
The use of insulin is hampered by its narrow therapeutic index. Although advances in both peptide chemistry and recombinant DNA-based expression have enabled the synthesis of structurally optimised insulin analogues (e.g. detemir, glargine), the growing epidemic of diabetes has emphasised the need for therapies that are more effective, safe and convenient, and that meet the demand for supply. The most commonly used insulin, glargine, causes weight gain, injection amyloidosis and exhibits six to eight times greater affinity for insulin-like growth factor 1 receptor (IGF-1R) compared with insulin leading to the potential risk of cancer over time. Therefore, there is an urgent need to develop high-yielding chemical methods as well as safer and efficacious long-acting insulin analogues.
This project will generate analogues that are selective to the insulin receptor, non-aggregating, and long-acting. We’ll use modern solid phase synthesis and regioselective disulfide bond formation to assemble peptides. We will use AFM to characterise the aggregation properties, and receptor binding/activation assays and appropriate animal models to evaluate their efficacy.