Biomimetic Synthesis of Lispro Insulin via a Chemically Synthesized “Mini-Proinsulin” Prepared by Oxime-Forming Ligation
- 16 October 2009
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 131 (44), 16313-16318
- https://doi.org/10.1021/ja9052398
Abstract
Here we report a proof-of-principle study demonstrating the efficient folding, with concomitant formation of the correct disulfides, of an isolated polypeptide insulin precursor of defined covalent structure. We used oxime-forming chemical ligation to introduce a temporary “chemical tether” to link the N-terminal residue of the insulin A chain to the C-terminal residue of the insulin B chain; the tether enabled us to fold/form disulfides with high efficiency. Enzymatic removal of the temporary chemical tether gave mature, fully active insulin. This chemical tethering principle could form the basis of a practical, high yield total synthesis of insulin and analogues.Keywords
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