Toward homogeneous erythropoietin: fine tuning of the C-terminal acyl donor in the chemical synthesis of the Cys29-Gly77 glycopeptide domain.
Described herein is the chemical synthesis of the Cys(29)-Gly(77) glycopeptide domain (22) of erythropoietin. Our initial ligation strategy targeted a C --> N termini condensation between glycopeptide 3 and peptide 4. However, the reaction was hindered by the "unattainable" reactivity, mismatched polarity, and severe aggregation of the (glyco)peptide substrates. In contrast, by tuning the C-terminal acyl donor and using smaller peptide fragments, the Cys(29)-Gly(77) glycopeptide domain of erythropoietin was prepared through unconventional N --> C termini condensation reactions. The use of a p-cyanonitrophenyl ester and the development of a masked thiophenyl ester as acyl donors enabled us to promptly access glycopeptides bearing complex carbohydrates and offer potential synthetic applications beyond our current work.
Yuan
Yu
Y
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA.
Chen
Jin
J
Wan
Qian
Q
Tan
Zhongping
Z
Chen
Gong
G
Kan
Cindy
C
Danishefsky
Samuel J
SJ
D000215:Acylation; D004921:Erythropoietin / Q000138:chemical synthesis*; D006020:Glycopeptides / Q000138:chemical synthesis*; D010446:Peptide Fragments / Q000138:chemical synthesis*; D010648:Phenylacetates; D011134:Polysaccharides; D017434:Protein Structure, Tertiary
D006020:Glycopeptides; D010446:Peptide Fragments; D010648:Phenylacetates; D011134:Polysaccharides; D004921:Erythropoietin; C012577:thiophenyl acetate