Novel four-disulfide insulin analog with high aggregation stability and potency
Autor: | Yi Wolf Zhang, Prasoona Karra, William L. Holland, Alan Blakely, Christopher P. Hill, Danny Hung-Chieh Chou, Matthew J. Webber, Gabrielle Ghabash, Michael A. VandenBerg, Xiaochun Xiong, Frank G. Whitby |
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Rok vydání: | 2019 |
Předmět: |
0303 health sciences
Chemistry Insulin medicine.medical_treatment Disulfide bond Insulin analog Insulin activity General Chemistry macromolecular substances Protein tertiary structure 03 medical and health sciences 0302 clinical medicine Biochemistry In vivo 030220 oncology & carcinogenesis medicine Potency 030304 developmental biology Hormone |
Zdroj: | Chemical Science |
ISSN: | 2041-6520 |
Popis: | A novel four-disulfide insulin analog was designed with retained bioactivity and increased fibrillation stability. Although insulin was first purified and used therapeutically almost a century ago, there is still a need to improve therapeutic efficacy and patient convenience. A key challenge is the requirement for refrigeration to avoid inactivation of insulin by aggregation/fibrillation. Here, in an effort to mitigate this problem, we introduced a 4th disulfide bond between a C-terminal extended insulin A chain and residues near the C-terminus of the B chain. Insulin activity was retained by an analog with an additional disulfide bond between residues A22 and B22, while other linkages tested resulted in much reduced potency. Furthermore, the A22-B22 analog maintains the native insulin tertiary structure as demonstrated by X-ray crystal structure determination. We further demonstrate that this four-disulfide analog has similar in vivo potency in mice compared to native insulin and demonstrates higher aggregation stability. In conclusion, we have discovered a novel four-disulfide insulin analog with high aggregation stability and potency. |
Databáze: | OpenAIRE |
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