Total Chemical Synthesis of Palmitoyl-Conjugated Insulin

Mengjie Liu, Qingyang Li, Carlie Delaine, Hongkang Wu, Yanni Arsenakis, Barbara F. White, Briony E. Forbes, Chaitra Chandrashekar, Mohammed Akhter Hossain

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Commercially available insulins are manufactured by recombinant methods for the treatment of diabetes. Long-acting insulin drugs (e.g., detemir and degludec) are obtained by fatty acid conjugation at LysB29 ϵ-amine of insulin via acid-amide coupling. There are three amine groups in insulin, and they all react with fatty acids in alkaline conditions. Due to the lack of selectivity, such conjugation reactions produce non-desired byproducts. We designed and chemically synthesized a novel thiol-insulin scaffold (CysB29-insulin II), by replacing the LysB29 residue in insulin with the CysB29 residue. Then, we conjugated a fatty acid moiety (palmitic acid, C16) to CysB29-insulin II by a highly efficient and selective thiol-maleimide conjugation reaction. We obtained the target peptide (palmitoyl-insulin) rapidly within 5 min without significant byproducts. The palmitoyl-insulin is shown to be structurally similar to insulin and biologically active both in vitro and in vivo. Importantly, unlike native insulin, palmitoyl-insulin is slow and long-acting.

Original languageEnglish
Pages (from-to)13715-13720
Number of pages6
JournalACS Omega
Issue number15
Publication statusPublished - 18 Apr 2023


  • diabetes management
  • insulin
  • palmitoyl-conjugated insulin


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