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A Synthetic Route to Human Insulin Using Isoacyl Peptides
Author(s) -
Liu Fa,
Luo Ethan Y.,
Flora David B.,
Mezo Adam R.
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201310735
Subject(s) - human insulin , dipeptide , insulin , peptide , yield (engineering) , native chemical ligation , chemistry , disulfide bond , combinatorial chemistry , chemical synthesis , chain (unit) , chemical ligation , peptide synthesis , biochemistry , biology , in vitro , materials science , microbiology and biotechnology , physics , astronomy , metallurgy
The chemical synthesis of insulin has been a longstanding challenge, mainly because of the notorious hydrophobicity of the A chain and the complicated topology of this 51‐mer peptide hormone consisting of two chains and three disulfide bonds. Reported herein is a new synthetic route utilizing the isoacyl peptide approach to address the hydrophobicity problems. The incorporation of isoacyl dipeptide segments into both A and B chains greatly improved their preparation and purification, and the RP‐HPLC recovery of the chain ligation intermediates. The new route affords human insulin with a yield of 68 % based on the starting purified A chain and an overall yield of 24 % based on the substitution of the resin used for the preparation of A chain. To the best of our knowledge, this represents the most efficient route of human insulin chemical synthesis reported to date.