Tokai University Research: High Efficiency Synthesis of Insulin by Self-assembly Based Organic Chemistry

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Insulin is a hormone that acts to lower the rise in blood glucose level after meals and is used as a therapeutic agent for diabetes. Since insulin has a characteristic molecular structure in which two peptide chains (A and B chains) are connected by two disulfide bridges (SS bonds), chemical synthesis has been considered as being difficult achieve. Currently, insulin is manufactured by a genetic engineering process.

Here, Michio Iwaoka at Tokai University, Japan, in collaboration with the groups of Hironobu Hojo at Osaka University and Kenji Inaba at Tohoku University, and Setsuko Ando at Fukuoka University, report on their success in efficiently synthesizing insulin by using only chemical processes based on organic synthesis.

The researchers have previously reported on the efficient chemical synthesis of insulin (seleno-insulin) in which selenocysteine was substituted for insulin containing cysteine to replace the SS bond between the peptide chains with a diselenide crosslink (SeSe bond) (Angew. Chem., Int. Ed., 2017, 56(20), 5522-5526).

In this paper, the researchers have improved on the previous synthesis method of seleno-insulin and produced natural insulin (bovine insulin) at a higher yield (of approximately 40%) than seleno-insulin. Furthermore, by applying this new method, they succeeded in the efficient chemical synthesis of insulin families such as human insulin and human type 2 relaxin.

In this research, the group first examined the process (oxidative folding pathway) by which insulin A chain and insulin B chain combine to form the structure of natural type insulin. Then, based on the pathway, they succeeded in optimizing folding conditions of bovine insulin and obtaining bovine insulin at high yield of about 40%.

The advantages of this synthesis method is that it does not require any large-scale production equipment because it does not use any genetic engineering technique and insulin can be produced by the simple process of mixing A chain and B chain-both of which can be synthesized by a solid phase peptide synthesis method using a resin.

"Using this 'self-assembly' approach it would be possible to modify the structure of insulin, such as introducing an unnatural amino acid into insulin," explains Iwaoka. "We expect that this method could be applied to the development of many types of insulin preparations such as long-acting and super quick-acting types."

Reference 

Kenta Arai, Toshiki Takei, Reina Shinozaki, Masato Noguchi, Shouta Fujisawa, Hidekazu Katayama, Luis Moroder, Setsuko Ando, Masaki Okumura, Kenji Inaba, Hironobu Hojo & Michio Iwaoka.

Characterization and optimization of two-chain folding pathways of insulin via native chain

Assembly. Communications Chemistry (2018) 1:26.

DOI: 10.1038/s42004-018-0024-0

About Tokai University 

Tokai University is a private university established by Shigeyoshi Matsumae in 1942. "Tokai" of "Tokai University" refers to the sea to the east of Asia, namely the Pacific Ocean, and symbolizes the desire to foster the kinds of big hearts, rich spirits, and broad perspectives symbolized by the expanse of an ocean.

The white cross of the school flag symbolizes "Love" and "Justice," and expresses the presence of "Truth" where love and justice meet.

The Tokai University Educational System is one of the largest general education and research institutions in Japan today. To seek mutual understanding and global peace through the education of, and interaction with, young scholars from around the world, we began accepting foreign students from an early stage and have consistently promoted Japanese-language education.

For more information, please visit
http://www.u-tokai.ac.jp/english/

Further information

Professor Michio Iwaoka
Department of Chemistry, School of Science
Tokai University,
4-1-1 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan
E-MAIL: miwaoka@tokai.ac.jp 
Tel: +81-(0)-463-58-1211 (ext 3747)