Structure–activity relationships of a peptide inhibitor of the human FcRn:human IgG interaction

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 12; pp. 6394 - 6405
• Main Authors: Mezo, Adam R., McDonnell, Kevin A., Castro, Alfredo, Fraley, Cara
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.06.2008; Elsevier Science
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Autoimmune disease; Biological and medical sciences; Consensus Sequence; FcRn; Histocompatibility Antigens Class I - metabolism; Humans; Immunoglobulin G - metabolism; Immunomodulators; Inhibition; Medical sciences; Molecular Sequence Data; Neonatal Fc receptor; Peptide antagonist; Peptides - chemistry; Peptides - pharmacology; Peptidomimetic; Pharmacology. Drug treatments; Receptors, Fc - antagonists & inhibitors; Receptors, Fc - metabolism; Structure-Activity Relationship; Surface Plasmon Resonance; FcRn; Autoimmune disease; Peptide antagonist; Neonatal Fc receptor; Inhibition; Peptidomimetic; Human; Oligopeptides; Peptides; Cyclic peptides; Peptidomimetic compound; In vitro; Structure activity relation; Polypeptide; Affinity; Antagonist
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.05.004

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.