Solid-phase synthesis and cyclization of a large branched peptide from IgG Fc with affinity for Fc gammaRI.
A solid phase approach has been used to synthesize a large branched disulphide peptide from IgG Fc, Ac-F-C*-A-K-V-N-N-K-D-L-P-A-P-I-E-K(Ac-E-L-L-G-G-P-S-V-F)-C*-I-NH2. This peptide combines the lower hinge region of IgG and a proximal beta-hairpin loop, both implicated in binding to Fc gammaRI. Solid phase Tl(tfa)3 cyclization of the linear branched peptide resulted in a poor yield of cyclic hinge-loop peptide (11%) most likely due to steric hindrance caused by the branch. However, if addition of the branch was preceded by solid phase Tl(tfa)3 cyclization of the loop, the yield was excellent at 75%. Cyclic hinge-loop peptide was active in displacing IgG2a from Fc gammaRI expressed on monocyte cell lines with an IC50 of 40 microM, whereas the linear form of this peptide was inactive. The Fc hinge-loop peptide demonstrates the potential for a non-mAb high affinity, immunomodulatory ligand for Fc gammaRI.
Sheridan
J M
JM
Department of Surgery, St George's Hospital Medical School, London, UK.
Hayes
G M
GM
Austen
B M
BM
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017452:Receptors, IgG / Q000737:chemistry* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D007074:Immunoglobulin G; D010446:Peptide Fragments; D017452:Receptors, IgG