Identification of cyclic peptides able to mimic the functional epitope of IgG1‐Fc for human FcyRI

Abstract

Identification of short, structured peptides able to mimic potently protein‐protein interfaces remains a challenge in drug discovery. We report here the use of a naive cyclic peptide phage display library to identify peptide ligands able to recognize and mimic IgG1‐Fc functions with FcyRI. Selection by competing off binders to FcyRI with IgG1 allowed the isolation of a family of peptides sharing the common consensus sequence TX 2 CXXØPXLLGCΦXE (Ø represents a hydrophobic residue, Φ is usually an acidic residue, and X is any residue) and able to inhibit IgG1 binding to FcγRI. In soluble form, these peptides antagonize superoxide generation mediated by IgG1. In complexed form, they trigger phagocytosis and a superoxide burst. Unlike IgG, these peptides are strictly FcγRI‐specific among the FcγRs. Molecular modeling studies suggest that these peptides can adopt 2 distinct and complementary conformers, each able to mimic the discontinuous interface contacts constituted by the Cγ2‐A and ‐B chains of Fc for FcγRI. In addition, by covalent homodimerization, we engineered a synthetic bivalent 37‐mer peptide that retains the ability to trigger effector functions. We demonstrate here that it is feasible to maintain IgG‐Fc function within a small structured peptide. These peptides represent a new format for modulation of effector functions.— Bonetto, S., Spadola, L., Buchanan, A. G., Jermutus, L. Lund, J. Identification of cyclic peptides able to mimic the functional epitope of IgG1‐Fc for human FcγRI. FASEB J. 23, 575–585 (2009)