Molecular design of functional domain-mimics of receptors and ligands

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We tested the approach to design the peptide mimics of the receptor/ligand-binding domain by panning a phage display library using their conformational epitope-recognizing monoclonal antibodies. We demonstrated the feasibility of this approach by the reports of Nature biotechnology (16 : 267-270, 1998) and J. Immunol. (161 : 6622-6628).In this study, we attempted to design the mimic molecule of MCP-1 (monocyte chemoattractant protein-1) and IL-6. In the case of MCP-1, we successfully identified the MCP-1 peptide mimic motifs of 19 amino acids, named G25 and C27. Both motifs contain two cysteins in their sequences. The synthetic and intramolecularly disulfide-linked peptides of these motifs inhibited the chemotaxis induced by MCP-1, while their derivatives with serine in place of cysteine did not.In the case of IL-6, we identified the #37 motif which specifically bound to human IL-6. The synthetic 13 amino acid peptide of #37 motif inhibited the proliferation of human KT-3 cell lines induced with the stimulation of IL-6. On the other hand, The #37 peptide showed no inhibition on the proliferation of murine MH60 which is the IL-6-dependent cell line.Thus, the G25, C27 and #37 peptide may be the leading peptides with antagonistic activities and useful for the therapy of inflammatory and autoimmune diseases such as rheumatoid arthritis.