Preparation of Selenoinsulin as a Long-Lasting Insulin Analogue

Kenta Arai, Toshiki Takei, Masaki Okumura, Satoshi Watanabe, Yuta Amagai, Yuya Asahina, Luis Moroder, Hironobu Hojo, Kenji Inaba, Michio Iwaoka

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

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 [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.

Original languageEnglish
Pages (from-to)5522-5526
Number of pages5
JournalAngewandte Chemie - International Edition
Volume56
Issue number20
DOIs
Publication statusPublished - 2017

Keywords

  • amino acids
  • drug discovery
  • protein folding
  • selenium
  • structure elucidation

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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