Small Peptide Mimics of Nerve Growth Factor Bind TrkA Receptors and Affect Biological Responses

Abstract

Small monomeric cyclic analogs that mimic the β-turn regions of nerve growth factor (NGF) were designed and synthesized. Potent competitive antagonists were derived from the NGF β-turn C-D, which inhibited [125I] NGF binding to TrkA receptors and specifically inhibited optimal NGF-mediated neurite outgrowth in PC12 cells. The cyclic β-turn A′-A″ analog also inhibited NGF binding to TrkA receptors but with lower potency. These data indicate that β-turns C-D and A′-A″ are critical for TrkA binding and may confer neurotrophin receptor specificity. Furthermore, structural requirements for binding are absolute, because unconstrained analogs derived from the same regions had no effect. Compounds that mimic NGF will be useful in deciphering the interactions of NGF and its receptors and in rational drug design. Small monomeric cyclic analogs that mimic the β-turn regions of nerve growth factor (NGF) were designed and synthesized. Potent competitive antagonists were derived from the NGF β-turn C-D, which inhibited [125I] NGF binding to TrkA receptors and specifically inhibited optimal NGF-mediated neurite outgrowth in PC12 cells. The cyclic β-turn A′-A″ analog also inhibited NGF binding to TrkA receptors but with lower potency. These data indicate that β-turns C-D and A′-A″ are critical for TrkA binding and may confer neurotrophin receptor specificity. Furthermore, structural requirements for binding are absolute, because unconstrained analogs derived from the same regions had no effect. Compounds that mimic NGF will be useful in deciphering the interactions of NGF and its receptors and in rational drug design. Small peptide mimics of nerve growth factor bind TrkA receptors and affect biological responses.Journal of Biological ChemistryVol. 271Issue 2PreviewPage 6568, Fig. 2: Due to an error in the use of a graphics program, panel A of this figure is incorrect. The published figure shows the same data set for unlabeled NGF and C(92-96) inhibitors depicted at different concentrations (compare the y axis intercept of each point for unlabeled NGF and C(92-96)). The correct figure is shown below. Full-Text PDF Open Access