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

Stephane Bonetto^*, Loredana Spadola, Andrew G. Buchanan^*, Lutz Jermutus^*,1 and John Lund^*,1

^* MedImmune, Research, Granta Park, Cambridge, UK; and

AstraZeneca R&D, DECS Global Compound Sciences, Mölndal, Sweden

¹Correspondence: MedImmune, Research, Granta Park, Milstein Bldg., Cambridge, CB21 6GH, UK. E-mail: J.L., lundj{at}medimmune.com; or L.J., jermutusl{at}medimmune.com

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 FcRI. Selection by competing off binders to FcRI with IgG1 allowed the isolation of a family of peptides sharing the common consensus sequence TX₂CXXPXLLGCXE ( represents a hydrophobic residue, is usually an acidic residue, and X is any residue) and able to inhibit IgG1 binding to FcRI. 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 FcRI-specific among the FcRs. 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 C2-A and -B chains of Fc for FcRI. 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 FcRI.

Key Words: effector functions • phage display • single-chain homodimer • molecular modeling • discontinuous interface • consensus sequence