Insulin Analogues with Altered Insulin Receptor Isoform Binding Specificities and Enhanced Aggregation Stabilities
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
MR/K000179/1
Medical Research Council - United Kingdom
MR/R009066/1
Medical Research Council - United Kingdom
- MeSH
- CD antigeny chemie metabolismus MeSH
- fosforylace MeSH
- inzulin analogy a deriváty metabolismus MeSH
- inzulinová rezistence MeSH
- kalorimetrie metody MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- protein - isoformy chemie metabolismus MeSH
- proteinové agregáty * MeSH
- receptor inzulinu chemie metabolismus MeSH
- sekvence aminokyselin MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- CD antigeny MeSH
- INSR protein, human MeSH Prohlížeč
- inzulin MeSH
- protein - isoformy MeSH
- proteinové agregáty * MeSH
- receptor inzulinu MeSH
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.
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