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Journal Article

Preparation of Selenoinsulin as a Long-Lasting Insulin Analogue


Moroder,  Luis
Moroder, Luis / Bioorganic Chemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Arai, K., Takei, T., Okumura, M., Watanabe, S., Amagai, Y., Asahina, Y., et al. (2017). Preparation of Selenoinsulin as a Long-Lasting Insulin Analogue. Angewandte Chemie International Edition, 56(20), 5522-5526. doi:10.1002/anie.201701654.

Cite as: http://hdl.handle.net/11858/00-001M-0000-002D-50EE-1
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 (t(1/2) approximate to 8 h vs. approximate to 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.