A peptidomimetic of NT-3 acts as a TrkC antagonist.
Neurotrophins are a family of growth factors that regulate the peripheral and central nervous system. We designed and tested a mini-library of small molecules peptidomimetics based on beta-turns of the neurotrophin growth factor polypeptides NT-3, which is the natural ligand for TrkC receptors. Biological studies identified a peptidomimetic 2Cl that exhibited selective antagonism of TrkC. 2Cl reduces TrkC activation and signaling promoted by NT-3, and selectively blocks ligand-dependent cell survival. 2Cl also blocks ligand-independent TrkC activation and signals that take place when the receptor is over-expressed. This work adds to our understanding of how the neurotrophins function through Trk receptors, and demonstrates that peptidomimetics can be designed to selectively disturb neurotrophin-receptor interactions, and receptor activation.
Brahimi
Fouad
F
Lady Davis Institute-Jewish General Hospital, McGill University, Canada.
Malakhov
Andrey
A
Lee
Hong Boon
HB
Pattarawarapan
Mookda
M
Ivanisevic
Lubijca
L
Burgess
Kevin
K
Saragovi
H Uri
HU
D000818:Animals; D002470:Cell Survival; D051379:Mice; D018716:Molecular Mimicry; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D020933:Neurotrophin 3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D020812:Receptor, trkC / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D020933:Neurotrophin 3; D010455:Peptides; D017526:Receptor, IGF Type 1; D020917:Receptor, trkA; D020812:Receptor, trkC