Insulin Analogues with Altered Insulin Receptor Isoform Binding Specificities and Enhanced Aggregation Stabilities

• Published in: Journal of medicinal chemistry Vol. 64; no. 19; pp. 14848 - 14859
• Main Authors: Páníková, Terezie, Mitrová, Katarína, Halamová, Tereza, Mrzílková, Karolína, Pícha, Jan, Chrudinová, Martina, Kurochka, Andrii, Selicharová, Irena, Žáková, Lenka, Jiráček, Jiří
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.10.2021
• Subjects: Amino Acid Sequence; Animals; Antigens, CD - chemistry; Antigens, CD - metabolism; Calorimetry - methods; Humans; Insulin - analogs & derivatives; Insulin - metabolism; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Phosphorylation; Protein Aggregates; Protein Binding; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Receptor, Insulin - chemistry; Receptor, Insulin - metabolism
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01388

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, [AlaB29,GluB31,amideB31]-insulin may be interesting for further clinical evaluation.