AI Article Synopsis
- Insulin remains essential for diabetes management, and there's a push for new analogues that behave more like natural insulin and are more stable.
- Researchers engineered 48 insulin analogues by modifying specific parts of the insulin structure to improve their effectiveness at binding to insulin receptors.
- One promising analogue showed over 3 times better binding to the metabolic insulin receptor and proved more resistant to aggregation and more effective in animal tests compared to regular human insulin, suggesting it could be worth exploring in clinical settings.
Article Abstract
Insulin is a lifesaver for millions of diabetic patients. There is a need for new insulin analogues with more physiological profiles and analogues that will be thermally more stable than human insulin. Here, we describe the chemical engineering of 48 insulin analogues that were designed to have changed binding specificities toward isoforms A and B of the insulin receptor (IR-A and IR-B). We systematically modified insulin at the C-terminus of the B-chain, at the N-terminus of the A-chain, and at A14 and A18 positions. We discovered an insulin analogue that has Cα-carboxyamidated Glu at B31 and Ala at B29 and that has a more than 3-fold-enhanced binding specificity in favor of the "metabolic" IR-B isoform. The analogue is more resistant to the formation of insulin fibrils at 37 °C and is also more efficient in mice than human insulin. Therefore, [Ala,Glu,amide]-insulin may be interesting for further clinical evaluation.
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| http://dx.doi.org/10.1021/acs.jmedchem.1c01388 | DOI Listing |
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