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

Balamurugan Dhayalan, Yen Shan Chen, Nelson B. Phillips, Mamuni Swain, Nischay K. Rege, Ali Mirsalehi, Mark Jarosinski, Faramarz Ismail-Beigi, Norman Metanis, Michael A. Weiss*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)4695-4700
Number of pages6
JournalChemistry - A European Journal
Volume26
Issue number21
DOIs
StatePublished - 9 Apr 2020

Bibliographical note

Publisher Copyright:
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

  • chemical protein synthesis
  • insulin
  • oxidative protein folding
  • selenocysteine
  • selenoprotein

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