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 nerve growth factor (NGF) were designed and synthesized. Potent competitive antagonists were derived from the NGF beta-turn C-D, which inhibited [125I] NGF binding to TrkA receptors and specifically inhibited optimal NGF-mediated neurite outgrowth in PC12 cells. The cyclic beta-turn 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 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.
LeSauteur
L
L
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Wei
L
L
Gibbs
B F
BF
Saragovi
H U
HU
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D051379:Mice; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D013329:Structure-Activity Relationship
D009414:Nerve Growth Factors; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA