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Title: Engineering of a Biologically Active Insulin Dimer.
Austin Authors: Liu, Mengjie;White, Barbara F;Praveen, Praveen;Li, Wenyi;Lin, Feng;Wu, Hongkang;Li, Rong;Delaine, Carlie;Forbes, Briony E;Wade, John D;Hossain, Mohammed Akhter
Affiliation: School of Chemistry, The University of Melbourne, Victoria 3010, Australia
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia
Discipline of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
The Florey Department of Neuroscience and Mental Health, The University Melbourne, Victoria 3010, Australia
Austin Health
Issue Date: 2021 2021
Publication information: Journal of medicinal chemistry 2021; 64(23): 17448-17454
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.
DOI: 10.1021/acs.jmedchem.1c01594
ORCID: 0000-0003-1944-5301
Journal: Journal of medicinal chemistry
PubMed URL: 34797669
Type: Journal Article
Appears in Collections:Journal articles

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