Synthesis and structure-activity relationships of dimeric peptide antagonists of the human immunoglobulin G-human neonatal Fc receptor (IgG-FcRn) interaction.
The neonatal Fc receptor, FcRn, regulates the half-life of IgG in vivo and may be a target in the treatment of autoimmune disease. Monomeric peptide antagonists of the human IgG-human FcRn interaction were dimerized using three different synthetic methodologies: thiol/alkyl halide coupling of unprotected peptides, reductive alkylation of unprotected peptides, and on-resin amide bond formation with protected peptides. It was found that dimerization of monomeric peptides increased the in vitro activity of the peptide monomers more than 200-fold. Human IgG catabolism experiments in human FcRn transgenic mice were used to assess the in vivo activity of peptide dimers that possessed different linkers, cyclizations, and affinities for FcRn. Overall, it was found that the linker joining two monomeric peptides had only a minor effect on the in vitro potency but that in vitro potency was predictive of in vivo activity.
McDonnell
Kevin A
KA
Syntonix Pharmaceuticals, Inc., a Subsidiary of Biogen Idec, 9 Fourth Avenue, Waltham, Massachusetts 02451, USA.
Low
Susan C
SC
Hoehn
Todd
T
Donnelly
Ryan
R
Palmieri
Holly
H
Fraley
Cara
C
Sakorafas
Paul
P
Mezo
Adam R
AR
D000818:Animals; D019281:Dimerization; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011961:Receptors, Fc; C100688:Fc receptor, neonatal