Biomimetic Synthesis of Lispro Insulin via a Chemically Synthesized "Mini-Proinsulin" Prepared by Oxime-Forming Ligation

Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
Journal of the American Chemical Society (Impact Factor: 12.11). 11/2009; 131(44):16313-8. DOI: 10.1021/ja9052398
Source: PubMed


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.

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