Reassessment of an Innovative Insulin Analogue Excludes Protracted Action yet Highlights the Distinction between External and Internal Diselenide Bridges

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...

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Bibliographic Details
Published in:Chemistry : a European journal 2020-04, Vol.26 (21), p.4695-4700
Main Authors: Dhayalan, Balamurugan, Chen, Yen‐Shan, Phillips, Nelson B., Swain, Mamuni, Rege, Nischay K., Mirsalehi, Ali, Jarosinski, Mark, Ismail‐Beigi, Faramarz, Metanis, Norman, Weiss, Michael A.
Format: Article
Language:English
Subjects:
Analogs
Animal models
Bridges
chemical protein synthesis
Chemistry
Diabetes mellitus
Disulfide bonds
Glutamyl endopeptidase
Insulin
Medical innovations
oxidative protein folding
Physicochemical properties
Proteolysis
Selenocysteine
selenoprotein
Serine
Serine proteinase
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Summary: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[C7UA, C7UB] 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 [C7UA, C7UB] does not confer protracted action, nonetheless its comparison to internal diselenide bridges promises to provide broad biophysical insight. A seleno‐analogue of bovine insulin, Se‐insulin[C7UA, C7UB], in which the external interchain disulfide bond A7−B7 was replaced by diselenide, preserves biological activity but does not augment stability, protect from proteolysis or confer protracted action.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.202000309