A new scaffold for amide ligation.
Highly chemoselective amide forming ligation reactions have facilitated the synthetic access to proteins and other amide-linked bioconjugates. In order to generalize this approach, a N(alpha)-2-phenyl ethanethiol scaffold has been developed to promote S to N acyl transfer in a manner analogous to native chemical ligation with N-terminal cysteine residues. Analysis of scaffold-mediated ligation reactions in aqueous solution indicate that the ligation rate at Xaa-Gly junctions is sufficient for the synthesis of large polypeptides. In addition, it was found that the ligation rate is independent of the stereocenter in the scaffold and S- to N-acyl transfer is rate limiting. These studies indicate that the N(alpha)-2-phenyl ethanethiol scaffold is a good candidate for the development of a ligation chemistry for the formation of Xaa-Gly peptides and other unhindered amides.
Marinzi
C
C
IBRM, National Research Council, Via Mario Bianco 9, 20131 Milan, Italy.
Bark
S J
SJ
Offer
J
J
Dawson
P E
PE
D000577:Amides / Q000138:chemical synthesis*; D005998:Glycine / Q000737:chemistry; D008722:Methods; D010455:Peptides / Q000138:chemical synthesis; D011506:Proteins / Q000138:chemical synthesis; D013438:Sulfhydryl Compounds / Q000737:chemistry
D000577:Amides; D010455:Peptides; D011506:Proteins; D013438:Sulfhydryl Compounds; C007638:ethanethiol; D005998:Glycine