De Novo Design and Synthesis of a -Turn Peptidomimetic Scaffold and Its Application as JNK3 Allosteric Ligand

Abstract

As a way to develop a neuroprotective agent for the JNK3-JIP1-binding site, peptidomimetics of JIP-1 as JNK3 allosteric regulators have been examined. The study consisted of in silico scaffold hopping, molecular docking, solution and solid-phase peptide syntheses, and K-d measurements using surface plasmon resonance. As a peptidomimetic of JIP1, heptamer mimetic 16 (K-d=2.72m) displayed a higher affinity than decamer JIP1 (K-d=23.6m). The high affinity of 16 implies that the characteristic -turn mimetic structure, phi-X-phi hydrophobic motif in 16, increased its affinity toward the JIP-site of JNK3.