Structure-Activity Relationship Study of Affinity Peptides for the Fc Site of Human Immunoglobulin G.

Immunoglobulin G (IgG)-binding peptides have been widely used in medicinal chemistry, particularly in the preparation of homogeneous antibody-drug conjugates (ADCs). The dissociation constant (Kd) and kinetic parameters (kon and koff) are critical determinants of peptide performance in such applications. In this study, we conducted a structure-activity relationship (SAR) analysis of the IgG-binding peptide 15-IgBP, focusing on Asp3, Tyr6, and Thr15, to identify more potent derivatives with favorable binding affinities and kinetic profiles. Peptides with appropriately tuned ionic structures exhibited rapid binding and release properties, whereas hydrophobic substitutions in solvent-exposed regions led to slower dissociation. By integrating these SAR findings, we identified the optimized affinity peptides, IAPG-2 and IAPG-3, with sub-nanomolar binding affinities (Kd = 0.753 and 0.705 nM, respectively).