| Autor: |
Nelson B, Phillips, Zhu-li, Wan, Linda, Whittaker, Shi-Quan, Hu, Kun, Huang, Qing-xin, Hua, Jonathan, Whittaker, Faramarz, Ismail-Beigi, Michael A, Weiss |
| Rok vydání: |
2010 |
| Předmět: |
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| Zdroj: |
The Journal of biological chemistry. 285(16) |
| ISSN: |
1083-351X |
| Popis: |
Bottom-up control of supramolecular protein assembly can provide a therapeutic nanobiotechnology. We demonstrate that the pharmacological properties of insulin can be enhanced by design of "zinc staples" between hexamers. Paired (i, i+4) His substitutions were introduced at an alpha-helical surface. The crystal structure contains both classical axial zinc ions and novel zinc ions at hexamer-hexamer interfaces. Although soluble at pH 4, the combined electrostatic effects of the substitutions and bridging zinc ions cause isoelectric precipitation at neutral pH. Following subcutaneous injection in a diabetic rat, the analog effected glycemic control with a time course similar to that of long acting formulation Lantus. Relative to Lantus, however, the analog discriminates at least 30-fold more stringently between the insulin receptor and mitogenic insulin-like growth factor receptor. Because aberrant mitogenic signaling may be associated with elevated cancer risk, such enhanced specificity may improve safety. Zinc stapling provides a general strategy to modify the pharmacokinetic and biological properties of a subcutaneous protein depot. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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