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Novel four-disulfide insulin analog with high aggregation stability and potency

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Abstract

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.

Graphical abstract: Novel four-disulfide insulin analog with high aggregation stability and potency

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Publication details

The article was received on 09 Sep 2019, accepted on 05 Nov 2019 and first published on 05 Nov 2019


Article type: Edge Article
DOI: 10.1039/C9SC04555D
Chem. Sci., 2020, Advance Article
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Novel four-disulfide insulin analog with high aggregation stability and potency

    X. Xiong, A. Blakely, P. Karra, M. A. VandenBerg, G. Ghabash, F. Whitby, Y. W. Zhang, M. J. Webber, W. L. Holland, C. P. Hill and D. H. Chou, Chem. Sci., 2020, Advance Article , DOI: 10.1039/C9SC04555D

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