title: Preparation of Selenoinsulin as a Long-Lasting Insulin Analogue.
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.
authors.affiliation: Department of Chemistry, School of Science, Tokai University, Kitakaname, Hiratsuka-shi, Kanagawa, 259-1292, Japan.
authors.forename: Kenta
authors.identifier: 0000-0003-0785-2559
authors.initials: K
authors.lastname: Arai
authors.affiliation: Department of Chemistry, School of Science, Tokai University, Kitakaname, Hiratsuka-shi, Kanagawa, 259-1292, Japan.|Institute for Protein Research, Osaka University, Yamadaoka, Suita-shi, Osaka, 565-0871, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Takei
authors.affiliation: Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Aoba-ku, Sendai, 2-1-1, Japan.
authors.forename: Masaki
authors.identifier: 0000-0001-8130-2470
authors.initials: M
authors.lastname: Okumura
authors.affiliation: Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Aoba-ku, Sendai, 2-1-1, Japan.
authors.forename: Satoshi
authors.identifier: 0000-0002-1130-0477
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Aoba-ku, Sendai, 2-1-1, Japan.
authors.forename: Yuta
authors.identifier: 0000-0002-2999-4622
authors.initials: Y
authors.lastname: Amagai
authors.affiliation: Institute for Protein Research, Osaka University, Yamadaoka, Suita-shi, Osaka, 565-0871, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Asahina
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152, Martinsried, Germany.
authors.forename: Luis
authors.identifier: 0000-0001-9570-5713
authors.initials: L
authors.lastname: Moroder
authors.affiliation: Institute for Protein Research, Osaka University, Yamadaoka, Suita-shi, Osaka, 565-0871, Japan.
authors.forename: Hironobu
authors.identifier: 0000-0003-0916-1233
authors.initials: H
authors.lastname: Hojo
authors.affiliation: Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Aoba-ku, Sendai, 2-1-1, Japan.
authors.forename: Kenji
authors.identifier: 0000-0001-8229-0467
authors.initials: K
authors.lastname: Inaba
authors.affiliation: Department of Chemistry, School of Science, Tokai University, Kitakaname, Hiratsuka-shi, Kanagawa, 259-1292, Japan.
authors.forename: Michio
authors.identifier: 0000-0002-6271-0185
authors.initials: M
authors.lastname: Iwaoka
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry; D007328:Insulin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry*; D008958:Models, Molecular
chemical_list: D004220:Disulfides; D007328:Insulin
keywords: amino acids; drug discovery; protein folding; selenium; structure elucidation