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Reassessment of an Innovative Insulin Analogue Excludes Protracted Action yet Highlights the Distinction between External and Internal Diselenide Bridges
Author(s) -
Dhayalan Balamurugan,
Chen YenShan,
Phillips Nelson B.,
Swain Mamuni,
Rege Nischay K.,
Mirsalehi Ali,
Jarosinski Mark,
IsmailBeigi Faramarz,
Metanis Norman,
Weiss Michael A.
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202000309
Subject(s) - insulin , insulin analog , oligopeptidase , protease , chemistry , proteolysis , novelty , diselenide , enzyme , medicine , biochemistry , endocrinology , psychology , human insulin , social psychology , selenium , organic chemistry
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.