Identification of cyclic peptides able to mimic the functional epitope of IgG1-Fc for human FcγRI

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 Fc gamma RI. Selection by competing off binders to Fc gamma RI with IgG1 allowed the isolation of a family of peptides sharing the common consensus sequence TX2CXX theta PXLLGC Phi XE (theta represents a hydrophobic residue, Phi is usually an acidic residue, and X is any residue) and able to inhibit IgG1 binding to Fc gamma RI. 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 Fc gamma RI-specific among the Fc gamma Rs. 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 C gamma 2-A and -B chains of Fc for Fc gamma RI. 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 Fc gamma RI. FASEB J. 23, 575-585 (2009)