Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity
Abstract Seleno-insulin, a class of artificial insulin analogs, in which one of the three disulfide-bonds (S-S’s) of wild-type insulin (Ins) is replaced by a diselenide-bond (Se-Se), is attracting attention for its unique chemical and physiological properties that differ from those of Ins. Previousl...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-023-01056-4 |
| _version_ | 1797453601689305088 |
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| author | Kenta Arai Masaki Okumura Young-Ho Lee Hidekazu Katayama Kenji Mizutani Yuxi Lin Sam-Yong Park Kaichiro Sawada Masao Toyoda Hironobu Hojo Kenji Inaba Michio Iwaoka |
| author_facet | Kenta Arai Masaki Okumura Young-Ho Lee Hidekazu Katayama Kenji Mizutani Yuxi Lin Sam-Yong Park Kaichiro Sawada Masao Toyoda Hironobu Hojo Kenji Inaba Michio Iwaoka |
| author_sort | Kenta Arai |
| collection | DOAJ |
| description | Abstract Seleno-insulin, a class of artificial insulin analogs, in which one of the three disulfide-bonds (S-S’s) of wild-type insulin (Ins) is replaced by a diselenide-bond (Se-Se), is attracting attention for its unique chemical and physiological properties that differ from those of Ins. Previously, we pioneered the development of a [C7UA,C7UB] analog of bovine pancreatic insulin (SeIns) as the first example, and demonstrated its high resistance against insulin-degrading enzyme (IDE). In this study, the conditions for the synthesis of SeIns via native chain assembly (NCA) were optimized to attain a maximum yield of 72%, which is comparable to the in vitro folding efficiency for single-chain proinsulin. When the resistance of BPIns to IDE was evaluated in the presence of SeIns, the degradation rate of BPIns became significantly slower than that of BPIns alone. Furthermore, the investigation on the intermolecular association properties of SeIns and BPIns using analytical ultracentrifugation suggested that SeIns readily forms oligomers not only with its own but also with BPIns. The hypoglycemic effect of SeIns on diabetic rats was observed at a dose of 150 μg/300 g rat. The strategy of replacing the solvent-exposed S-S with Se-Se provides new guidance for the design of long-acting insulin formulations. |
| first_indexed | 2024-03-09T15:25:11Z |
| format | Article |
| id | doaj.art-3b226a8eb62b476ba0aaef9ad91a6b1c |
| institution | Directory Open Access Journal |
| issn | 2399-3669 |
| language | English |
| last_indexed | 2024-03-09T15:25:11Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj.art-3b226a8eb62b476ba0aaef9ad91a6b1c2023-11-26T12:34:02ZengNature PortfolioCommunications Chemistry2399-36692023-11-016111010.1038/s42004-023-01056-4Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activityKenta Arai0Masaki Okumura1Young-Ho Lee2Hidekazu Katayama3Kenji Mizutani4Yuxi Lin5Sam-Yong Park6Kaichiro Sawada7Masao Toyoda8Hironobu Hojo9Kenji Inaba10Michio Iwaoka11Department of Chemistry, School of Science, Tokai UniversityFrontier Research Institute for Interdisciplinary Sciences, Tohoku UniversityResearch Center for Bioconvergence Analysis, Korea Basic Science InstituteDepartment of Bioengineering, School of Engineering, Tokai UniversityDrug Design Laboratory, Graduate School of Medical Life Science, Yokohama City UniversityResearch Center for Bioconvergence Analysis, Korea Basic Science InstituteDrug Design Laboratory, Graduate School of Medical Life Science, Yokohama City UniversityDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Tokai University, School of MedicineDivision of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Tokai University, School of MedicineInstitute for Protein Research, Osaka UniversityInstitute of Multidisciplinary Research for Advanced Materials, Tohoku UniversityDepartment of Chemistry, School of Science, Tokai UniversityAbstract Seleno-insulin, a class of artificial insulin analogs, in which one of the three disulfide-bonds (S-S’s) of wild-type insulin (Ins) is replaced by a diselenide-bond (Se-Se), is attracting attention for its unique chemical and physiological properties that differ from those of Ins. Previously, we pioneered the development of a [C7UA,C7UB] analog of bovine pancreatic insulin (SeIns) as the first example, and demonstrated its high resistance against insulin-degrading enzyme (IDE). In this study, the conditions for the synthesis of SeIns via native chain assembly (NCA) were optimized to attain a maximum yield of 72%, which is comparable to the in vitro folding efficiency for single-chain proinsulin. When the resistance of BPIns to IDE was evaluated in the presence of SeIns, the degradation rate of BPIns became significantly slower than that of BPIns alone. Furthermore, the investigation on the intermolecular association properties of SeIns and BPIns using analytical ultracentrifugation suggested that SeIns readily forms oligomers not only with its own but also with BPIns. The hypoglycemic effect of SeIns on diabetic rats was observed at a dose of 150 μg/300 g rat. The strategy of replacing the solvent-exposed S-S with Se-Se provides new guidance for the design of long-acting insulin formulations.https://doi.org/10.1038/s42004-023-01056-4 |
| spellingShingle | Kenta Arai Masaki Okumura Young-Ho Lee Hidekazu Katayama Kenji Mizutani Yuxi Lin Sam-Yong Park Kaichiro Sawada Masao Toyoda Hironobu Hojo Kenji Inaba Michio Iwaoka Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity Communications Chemistry |
| title | Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity |
| title_full | Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity |
| title_fullStr | Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity |
| title_full_unstemmed | Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity |
| title_short | Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity |
| title_sort | diselenide bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity |
| url | https://doi.org/10.1038/s42004-023-01056-4 |
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