Selective small molecule peptidomimetic ligands of TrkC and TrkA receptors afford discrete or complete neurotrophic activities.
We designed a minilibrary of 55 small molecule peptidomimetics based on beta-turns of the neurotrophin growth factor polypeptides neurotrophin-3 (NT-3) and nerve growth factor (NGF). Direct binding, binding competition, and biological screens identified agonistic ligands of the ectodomain of the neurotrophin receptors TrkC and TrkA. Agonism is intrinsic to the peptidomimetic ligand (in the absence of neurotrophins), and/or can also be detected as potentiation of neurotrophin action. Remarkably, some peptidomimetics afford both neurotrophic activities of cell survival and neuronal differentiation, while others afford discrete signals leading to either survival or differentiation. The high rate of hits identified suggests that focused minilibraries may be desirable for developing bioactive ligands of cell surface receptors. Small, selective, proteolytically stable ligands with defined biological activity may have therapeutic potential.
Zaccaro
Maria Clara
MC
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Lee
Hong Boon
HB
Pattarawarapan
Mookda
M
Xia
Zebin
Z
Caron
Antoine
A
L'Heureux
Pierrre-Jean
PJ
Bengio
Yoshua
Y
Burgess
Kevin
K
Saragovi
H Uri
HU
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D007700:Kinetics; D008024:Ligands; D051379:Mice; D018716:Molecular Mimicry; D041681:NIH 3T3 Cells; D016716:PC12 Cells; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D020917:Receptor, trkA / Q000819:agonists / Q000378:metabolism*; D020812:Receptor, trkC / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D008024:Ligands; D010455:Peptides; D020917:Receptor, trkA; D020812:Receptor, trkC