Abstract:
:Brain-derived neurotrophic factor (BDNF) promotes the survival of various neuronal populations and thus shows potential in the treatment of neurodegenerative disease. However, BDNF is not pharmacokinetically optimal for use as a therapeutic agent. As a step toward the development of low-molecular-weight BDNF-like drugs, we have designed a series of small, conformationally constrained peptides of various sizes using the three-dimensional structure of BDNF derived by homology modeling as a template. When tested in cultures of embryonic chick sensory neurons the peptides produced concentration-dependent inhibition of BDNF-mediated neuronal survival and caused both a rightward shift and depression of the maximum of the BDNF concentration-response curve. The compounds had no effect on the survival response to nerve growth factor and were without intrinsic trophic or toxic effects when added to cultures alone. With the aid of pharmacodynamic simulations we demonstrated that the inhibitory activity of the active peptides is consistent with them acting as competitive antagonists of BDNF for its high-affinity receptor, trkB. An alanine scan of the largest peptide identified several residues important in mediating the inhibitory action of the peptides. We intend to use the data from these studies to develop small peptidic BDNF-like agonists.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
O'Leary PD,Hughes RAdoi
10.1046/j.1471-4159.1998.70041712.xsubject
Has Abstractpub_date
1998-04-01 00:00:00pages
1712-21issue
4eissn
0022-3042issn
1471-4159journal_volume
70pub_type
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1985.tb07191.x
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pub_type: 杂志文章
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1992.tb09378.x
更新日期:1992-03-01 00:00:00
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1999.0730372.x
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journal_title:Journal of neurochemistry
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