Osaka: Researchers at Tokai University, Osaka University, Tohoku University and Fukuoka University report in the journal Communications Chemistry on the synthesis of insulin based on the self-assembly of polypeptide chains at about 40% efficiency. This new approach is expected to enable flexibility in synthesizing order made insulin compounds that cannot be produced using conventional biological approaches based on genetic engineering. 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).
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 (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.”
Caption: A simple protocol developed for insulin preparation.
To learn more about this research, please view the full research
report entitled "Characterization and optimization of two-chain
folding pathways of insulin via native chain assembly " a of Communications Chemistry.