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Preparation of Selenoinsulin as a Long‐Lasting Insulin Analogue
Author(s) -
Arai Kenta,
Takei Toshiki,
Okumura Masaki,
Watanabe Satoshi,
Amagai Yuta,
Asahina Yuya,
Moroder Luis,
Hojo Hironobu,
Inaba Kenji,
Iwaoka Michio
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201701654
Subject(s) - diselenide , insulin , chemistry , disulfide bond , stereochemistry , biochemistry , selenium , endocrinology , organic chemistry , biology
Synthetic insulin analogues with a long lifetime are current drug targets for the therapy of diabetic patients. The replacement of the interchain disulfide with a diselenide bridge, which is more resistant to reduction and internal bond rotation, can enhance the lifetime of insulin in the presence of the insulin‐degrading enzyme (IDE) without impairing the hormonal function. The [C7U A ,C7U B ] variant of bovine pancreatic insulin (BPIns) was successfully prepared by using two selenocysteine peptides (i.e., the C7U analogues of A‐ and B‐chains, respectively). In a buffer solution at pH 10 they spontaneously assembled under thermodynamic control to the correct insulin fold. The selenoinsulin (Se‐Ins) exhibited a bioactivity comparable to that of BPIns. Interestingly, degradation of Se‐Ins with IDE was significantly decelerated ( τ 1/2 ≈8 h vs. ≈1 h for BPIns). The lifetime enhancement could be due to both the intrinsic stability of the diselenide bond and local conformational changes induced by the substitution.