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J. Biol. Chem., Vol. 283, Issue 21, 99917, May 23, 2008

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Novel Approach to Insulin Therapy

After cleavage of the proinsulin precursor, the insulin molecule comprises two peptide chains held together by disulfide bonds. As the mature protein is susceptible to degradation, single-chain insulin (SCI) analogs with improved stability have been developed for biophysical and other experiments. However, while structurally similar to insulin, SCIs have generally had poor receptor binding due to linker hindrance. In this Paper of the Week, Qing-xin Hua and colleagues revisited the properties and shortcomings of previous SCIs in the design of their new ultrastable analog SCI-57. They bridged the two chains with a 6-residue glycine-rich linker (GGGPRR) and made four amino acid replacements that add negative charge to restore electrostatic balance, prevent self-assembly, and improve receptor affinity. SCI-57 assumed a native-like fold and showed remarkable thermodynamic stability relative to that of endogenous insulin (1.9 kcal/mol more energy required to unfold) while retaining native binding affinity (130% of wild-type). In addition to its use in biophysical applications, Hua and colleagues believe this active and ultrastable SCI may be extremely valuable for insulin therapy in the developing world and anywhere that lacks reliable refrigeration.

Front and back views of the engineered ultrastable single-chain insulin analog superimposed over a model of DKP-insulin (shown in black).

FOOTNOTES

See referenced article, J. Biol. Chem. 2008, 283, 14703-14716

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Related Collections Papers Of The Week Social Bookmarking                      What's this?