Abstract
A proteolytically stable small molecule β-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 β-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.
Footnotes
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Send reprint requests to: Dr. H. Uri Saragovi, McGill University, Pharmacology and Therapeutics, 3655 Drummond St., #1320, Montréal, Québec, Canada, H3G 1Y6. E-mail:Uri{at}pharma.mcgill.ca
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Supported by a grant of the Medical Research Council of Canada (to H.U.S.) and by National Institutes of Health Grants GM 50772 and CA 82642 (to K.B.), the Advanced Texas Research Program, and The Robert Welch Foundation. H.U.S. is a Scholar of the Pharmaceutical Manufacturer's Association of Canada-Medical Research Council of Canada.
- Abbreviations:
- NGF
- nerve growth factor
- BDNF
- brain-derived neurotrophic factor
- BOC
- tert-butoxycarbonyl
- ChAT
- choline acetyl transferase
- DMF
- dimethylformamide
- DRG
- dorsal root ganglia
- ELISA
- enzyme-linked immunosorbent assay
- FACScan
- fluorescent activated cell scanner
- FITC
- fluorescein isothiocyanate
- FMOC
- fluorenyloxycarbonyl
- MCF
- mean channel fluorescence
- MTT
- 3(4,5-dimethylthiazolyl-2)-2,5-diphenyl tetrazolium bromide
- NT-3
- neurotrophin-3
- RIA
- radioimmunoassay
- TFA
- trifluoroacetic acid
- Trt
- trityl
- ECD
- extracellular domain
- mAb
- monoclonal antibody
- HEK
- human embryonic kidney
- BB
- binding buffer
- OD
- optical density
- Received September 2, 1999.
- Accepted November 2, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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