Engineering of a Biologically Active Insulin Dimer

Mengjie Liu, Barbara F. White, Praveen Praveen, Wenyi Li, Feng Lin, Hongkang Wu, Rong Li, Carlie Delaine, Briony E. Forbes, John D. Wade, Mohammed Akhter Hossain

Research output: Contribution to journalArticlepeer-review

Abstract

The growing epidemic of diabetes means that there is a need for therapies that are more efficacious, safe, and convenient. Here, we report the efficient synthesis of a novel disulfide dimer of human insulin tethered at the N-terminus of its B-chain through placement of a cysteine residue. The resulting peptide was shown to bind to both the insulin receptor isoform B and insulin-like growth factor-1 receptor with comparable affinity to native insulin. In in vivo insulin tolerance tests, the dimer was equipotent to Actrapid insulin and possessed a sustained duration of action greater than that of Actrapid and Glargine. While the secondary structure of our dimeric insulin was similar to that of insulin, it was more resistant to proteolysis. More importantly, our analogue was produced in quantitative yield from a monomeric thiol insulin scaffold. Our results suggest that this dimer has significant potential to address the clinical needs in the treatment of diabetes.

Original languageEnglish
Pages (from-to)17448-17454
Number of pages7
JournalJournal of Medicinal Chemistry
Volume64
Issue number23
DOIs
Publication statusPublished - 9 Dec 2021

Keywords

  • Thiols
  • Peptides and proteins
  • Carbohydrates
  • Oligomers
  • Receptors

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