Promising general solution to the problem of ligating peptides and glycopeptides.
Our global goal is that of synthesizing complex polypeptides and glycopeptides in homogeneous form. Chemistry-derived access to homogeneous biologics could well have useful consequences in the discovery of drugs and vaccines. The key finding in this study is that thio acids can become highly competent acyl donors following even trace levels of oxidative activation, thereby undergoing amide bond formation upon reaction with N-terminal peptides. Though our data set does not establish the specific mechanism of this reaction, a framework to account for the fact that minute levels of oxidation actuate amide bond formation with high turnover is offered. An apparently general coupling of thio acids (including complex peptide thio acids with N-termini of complex peptides) has thus been realized. These ligations are conducted with minimal α-epimerization in the C-terminal group and allow for the coupling of N-terminal and C-terminal glycopeptides en route to homogeneous glycoproteins.
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA.
Ping
P
Wang
Samuel J
SJ
Danishefsky
D000595:Amino Acid Sequence; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D008969:Molecular Sequence Data; D014230:Triazoles / Q000737:chemistry
D006020:Glycopeptides; D014230:Triazoles; C011852:1-hydroxybenzotriazole