Design and Folding of [Glu~(A4)(O~βThr~(B30))]InsuIin ('Ester Insulin'): A Minimal Proinsulin Surrogate that Can Be Chemically Converted into Human Insulin

摘要

Insulin biosynthesis involves the efficient folding of a single polypeptide-chain precursor with concomitant formation of three disulfide bonds to give proinsulin followed by enzymatic removal of the C peptide to give mature insulin. A proinsulin- or miniproinsulin-based approach is currently used in the recombinant production of human insulin. However, recombinant production of insulin analogues is effectively limited to the creation of mutants from the twenty genetically encoded amino acids. In contrast to this, total chemical synthesis of insulin would in principle enable the incorporation of a wide range of nonnatural amino acids and other chemical modifications into the molecule, and would thus enable the full exploration of the medicinal chemistry of this important therapeutic molecule.