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- Title
Identification of cyclic peptides able to mimic the functional epitope of IgG1-Fc for human FcγRI.
- Authors
Bonetto, Stephane; Spadola, Loredana; Buchanan, Andrew G.; Jermutus, Lutz; Lund, John
- 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 identify peptide ligands able to recognize and mimic IgG1-Fc functions with Fcγ/RI. Selection by competing off binders to Fcγ/RI with IgG1 allowed the isolation a family of peptides sharing the common consensus sequence TX2CXXΘPXLLGCΦXE (O represents a hydrophobic residue, Φ is usually an acidic residue, and is any residue) and able to inhibit IgG1 binding 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.
- Subjects
CYCLIC peptides; EPITOPES; IMMUNOGLOBULIN G; DRUG development; PROTEIN-protein interactions; LIGANDS (Biochemistry)
- Publication
FASEB Journal, 2009, Vol 23, Issue 2, p575
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.08-117069