title: Structure-activity relationships of a peptide inhibitor of the human FcRn:human IgG interaction.
abstract: A family of five peptides was previously discovered by phage display techniques that binds to the human neonatal Fc receptor (FcRn) and inhibits the human IgG:human FcRn protein-protein interaction [Proc. Nat. Acad. Sci. U.S.A.2008, 105, 2337-2342]. The consensus peptide motif consists of the sequence GHFGGXY where X is preferably a hydrophobic amino acid, and also includes a disulfide bridge enclosing 11-amino acids in varying positions about the consensus sequence. We describe herein the structure-activity relationships of one of the five peptides in binding to FcRn using surface plasmon resonance and IgG:FcRn competition ELISA assays. Modifications of the peptide length, cyclization, and the incorporation of amino acid substitutions and dipeptide mimetics were studied. The most potent analogs exhibited a 50- to 100-fold improvement of in vitro activity over that of the phage-identified peptide sequence.
authors.affiliation: Syntonix Pharmaceuticals, Inc., 9 Fourth Avenue, Waltham, MA 02451, USA. amezo@syntnx.com
authors.forename: Adam R
authors.initials: AR
authors.lastname: Mezo
authors.forename: Kevin A
authors.initials: KA
authors.lastname: McDonnell
authors.forename: Alfredo
authors.initials: A
authors.lastname: Castro
authors.forename: Cara
authors.initials: C
authors.lastname: Fraley
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D016384:Consensus Sequence; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011961:Receptors, Fc / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D010455:Peptides; D011961:Receptors, Fc; C100688:Fc receptor, neonatal