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  Preparation of Selenoinsulin as a Long-Lasting Insulin Analogue

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.

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 Creators:
Arai, Kenta1, Author
Takei, Toshiki1, Author
Okumura, Masaki1, Author
Watanabe, Satoshi1, Author
Amagai, Yuta1, Author
Asahina, Yuya1, Author
Moroder, Luis2, Author              
Hojo, Hironobu1, Author
Inaba, Kenji1, Author
Iwaoka, Michio1, Author
Affiliations:
1external, ou_persistent22              
2Moroder, Luis / Bioorganic Chemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565160              

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Free keywords: TYPE-2 DIABETES-MELLITUS; CYSTINE-RICH PEPTIDES; DEGRADING ENZYME; ALZHEIMERS-DISEASE; KINETIC TRAP; SELENOCYSTINE; REPLACEMENT; DEGRADATION; INHIBITION; MANAGEMENTChemistry; amino acids; drug discovery; protein folding; selenium; structure elucidation;
 Abstract: 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.

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Language(s): eng - English
 Dates: 2017-04-102017
 Publication Status: Published in print
 Pages: 5
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000400458700019
DOI: 10.1002/anie.201701654
 Degree: -

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Title: Angewandte Chemie International Edition
  Other : Angew. Chem., Int. Ed.
  Other : Angew. Chem. Int. Ed.
  Other : Angewandte Chemie, International Edition
Source Genre: Journal
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Publ. Info: Weinheim : Wiley-VCH
Pages: - Volume / Issue: 56 (20) Sequence Number: - Start / End Page: 5522 - 5526 Identifier: ISSN: 1433-7851
CoNE: https://pure.mpg.de/cone/journals/resource/1433-7851