期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 56, 期 20, 页码 5522-5526出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201701654
关键词
amino acids; drug discovery; protein folding; selenium; structure elucidation
资金
- Japan Society for the Promotion of Science (JSPS)
- KAKENHI Grant [26888016]
- Tokai University, Educational System General Research Organization
- Cooperative Research Program of Institute for Protein Research, Osaka University [CR-15-01]
- Cooperative Research Program of Network Joint Research Center for Materials and Devices
- CREST, JST [JPMJCR13M6]
- MEXT [26116005, 15641922]
- Takeda Science Foundation
- Uehara Memorial Foundation
- Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Japan Agency for Medical Research and Development (AMED) [1017]
- Grants-in-Aid for Scientific Research [16H04180, 26116005, 17K18123, 17K05792, 26888016] Funding Source: KAKEN
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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