Angewandte Chemie - International Edition
Angewandte Chemie - International Edition
5 years ago

Preparation of Selenoinsulin as a Long-Lasting Insulin Analogue

Preparation of Selenoinsulin as a Long-Lasting Insulin Analogue
Toshiki Takei, Kenta Arai, Hironobu Hojo, Masaki Okumura, Luis Moroder, Michio Iwaoka, Yuya Asahina, Satoshi Watanabe, Yuta Amagai, Kenji Inaba
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 [C7UA,C7UB] 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 (τ1/2≈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. Long-lasting insulin, the selenium analogue [selenoinsulin (Se-Ins)] of bovine pancreatic insulin (BPIns), is a [C7UA,C7UB] variant and has a structure and a bioactivity comparable to that of BPIns. Degradation of Se-Ins with insulin-degrading enzyme (IDE) was significantly decelerated (τ1/2≈8 h vs. ≈1 h for BPIns). The lifetime enhancement is not only a result of the intrinsic stability of a Se−Se bond but also the local conformational changes induced by the substitution.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201701654

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