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Year : 2013  |  Volume : 1  |  Issue : 2  |  Page : 59-70

Design of ultra-stable insulin analogues for the developing world


Departments of Biochemistry, Biomedical Engineering and Medicine, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio, USA

Correspondence Address:
Michael A Weiss
Biomedical Engineering and Medicine, Case Western Reserve University School of Medicine, Wood W-437, 10900 Euclid Avenue, Cleveland, Ohio, 44106-4935
USA
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Source of Support: This work was supported by grants from the National Institutes of Health (DK040949, DK069764, DK089934, and DK079233) and American Diabetes Association to the author., Conflict of Interest: The author hold shares in and is Chief Scienti.c Officer of Thermalin Diabetes, LLC.; he has also been a consultant to Merck, Inc. and the DEKA Research and Development Corp. The author otherwise declares that the article was written in the absence of any commercial or .nancial relationships that could be construed as a potential con.ict of interest.

DOI: 10.4103/1658-600X.114683

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DOI: 10.4103/1658-600X.114683

Rights and Permissions

The engineering of insulin analogues illustrates the application of structure-based protein design to clinical medicine. Such design has traditionally been based on structures of wild-type insulin hexamers in an effort to optimize the pharmacokinetic (PK) and pharmacodynamic properties of the hormone. Rapid-acting insulin analogues (in chronological order of their clinical introduction, Humalog ® [Eli Lilly & Co.], Novolog ® [Novo-Nordisk], and Apidra ® [Sanofi-Aventis]) exploit the targeted destabilization of subunit interfaces to facilitate capillary absorption. Conversely, long-acting insulin analogues exploit the stability of the insulin hexamer and its higher-order self-assembly within the subcutaneous depot to enhance basal glycemic control. Current products either operate through isoelectric precipitation (insulin glargine, the active component of Lantus ® ; Sanofi-Aventis) or employ an albumin-binding acyl tether (insulin detemir, the active component of Levemir ® ; Novo-Nordisk). Such molecular engineering has often encountered a trade-off between PK goals and product stability. Given the global dimensions of the diabetes pandemic and complexity of an associated cold chain of insulin distribution, we envisage that concurrent engineering of ultra-stable protein analogue formulations would benefit the developing world, especially for patients exposed to high temperatures with inconsistent access to refrigeration. We review the principal mechanisms of insulin degradation above room temperature and novel molecular approaches toward the design of ultra-stable rapid-acting and basal formulations.


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