Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 26, Issue 21, Pages 4695-4700Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202000309
Keywords
chemical protein synthesis; insulin; oxidative protein folding; selenocysteine; selenoprotein
Categories
Funding
- Israel Science Foundation [783/18]
- ICRF Acceleration Grant
- U.S. National Institutes of Health [NIH R01 DK040949]
- NIH [5T32GM007250-38, 1F30DK112644]
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Long-acting insulin analogues represent the most prescribed class of therapeutic proteins. An innovative design strategy was recently proposed: diselenide substitution of an external disulfide bridge. This approach exploited the distinctive physicochemical properties of selenocysteine (U). Relative to wild type (WT), Se-insulin[C7U(A), C7U(B)] was reported to be protected from proteolysis by insulin-degrading enzyme (IDE), predicting prolonged activity. Because of this strategy's novelty and potential clinical importance, we sought to validate these findings and test their therapeutic utility in an animal model of diabetes mellitus. Surprisingly, the analogue did not exhibit enhanced stability, and its susceptibility to cleavage by either IDE or a canonical serine protease (glutamyl endopeptidase Glu-C) was similar to WT. Moreover, the analogue's pharmacodynamic profile in rats was not prolonged relative to a rapid-acting clinical analogue (insulin lispro). Although [C7U(A), C7U(B)] does not confer protracted action, nonetheless its comparison to internal diselenide bridges promises to provide broad biophysical insight.
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