SMALL PEPTIDE MIMICS OF NERVE GROWTH-FACTOR BIND TRKA RECEPTORS AND AFFECT BIOLOGICAL RESPONSES

Small monomeric cyclic analogs that mimic the beta-turn regions of ner ve growth factor (NGF) were designed and synthesized. Potent competiti ve antagonists were de rived from the NGF beta-turn C-D, which inhibit ed [I-125] NGF binding to TrkA receptors and specifically inhibited op timal NGF-mediated neurite outgrowth in PC12 cells. The cyclic beta-tu rn A'-A'' analog also inhibited NGF binding to TrkA receptors but with lower potency. These data indicate that beta-turns C-D and A'-A'' are critical for TrkA binding and may confer neurotrophin receptor specif icity. Furthermore, structural requirements for binding are absolute, because unconstrained analogs derived from the same regions had no eff ect. Compounds that mimic NGF will be useful in deciphering the intera ctions of NGF and its receptors and in rational drug design.