A designed peptidomimetic agonistic ligand of TrkA nerve growth factor receptors.
A proteolytically stable small molecule beta-turn peptidomimetic, termed D3, was identified as an agonist of the TrkA neurotrophin receptor. D3 binds the Ig-like C2 region of the extracellular domain of TrkA, competes the binding of another TrkA agonist, affords selective trophic protection to TrkA-expressing cell lines and neuronal primary cultures, and induces the differentiation of primary neuronal cultures. These results indicate that a small beta-turn peptidomimetic can activate a tyrosine kinase neurotrophin receptor that normally binds a relatively large protein ligand. Agents such as D3 that bind the extracellular domain of Trk receptors will be useful pharmacological agents to address disorders where Trk receptors play a role, by targeting populations selectively.
Maliartchouk
S
S
Department of Pharmacology, McGill University, Montréal, Quebec, Canada H3G 1Y6.
Feng
Y
Y
Ivanisevic
L
L
Debeir
T
T
Cuello
A C
AC
Burgess
K
K
Saragovi
H U
HU
D000818:Animals; D001667:Binding, Competitive; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D019281:Dimerization; D005333:Fetus / Q000166:cytology / Q000187:drug effects; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008024:Ligands; D018716:Molecular Mimicry; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010447:Peptide Hydrolases / Q000378:metabolism; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D051381:Rats; D020917:Receptor, trkA / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism
C404517:D3 compound; D008024:Ligands; D009414:Nerve Growth Factors; D019151:Peptide Library; D010456:Peptides, Cyclic; D020917:Receptor, trkA; D010447:Peptide Hydrolases