Design of MHC class II (DR4) ligands using conformationally restricted imino acids at p3 and p5

High potency synthetic ligands were designed for rheumatoid arthritis linked Class II MHC, DR4 Dw4. The design strategy utilized isosteric replacements at the p1 and p7 positions and conformational restriction with imino acids pipecolic acid (Pec) and proline at the solvent exposed residues p3 and p5. In particular, SC-67655, (S)-CBA-Val-Pec-Asp-Pro-Thr-NH-n-Pr (IC50 = 50 nM) is a potent and stable pentapeptide DR4 ligand.