Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 123, Issue 4, Pages 526-533Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja003265m
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- NIGMS NIH HHS [GM59380] Funding Source: Medline
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The highly chemoselective reaction between unprotected peptides bearing an N-terminal Cys residue and a C-terminal thioester enables the total and semi-synthesis of complex polypeptides. Here we extend the utility of this native chemical ligation approach to non-cysteine containing peptides. Since alanine is a common amino acid in proteins, ligation at this residue would be of great utility. To achieve this goal, a specific alanine residue in the parent protein is replaced with cysteine to facilitate synthesis by native chemical ligation. Following ligation, selective desulfurization of the resulting unprotected polypeptide product with H-2/metal reagents converts the cysteine residue to alanine. This approach, which provides a general method to prepare alanyl proteins from their cysteinyl forms, can be used to chemically synthesize a variety of polypeptides, as demonstrated by the total chemical syntheses of the cyclic antibiotic microcin J25, the 56-amino acid streptococcal protein G B1 domain, and a variant of the 110-amino acid ribonuclease, barnase.
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