Structure-Activity Relationships of Conformationally Constrained Peptide Analogues of Loop 2 of Brain-Derived Neurotrophic Factor
| Autor: | Paul D. O'Leary, Richard A. Hughes |
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| Rok vydání: | 2002 |
| Předmět: |
Models
Molecular Chemical Phenomena Cell Survival Protein Conformation Molecular Sequence Data Chick Embryo Tropomyosin receptor kinase B Biochemistry Mice Structure-Activity Relationship Cellular and Molecular Neuroscience chemistry.chemical_compound Neurotrophic factors Peptide synthesis Animals Computer Simulation Amino Acid Sequence Neurons Afferent Peptide sequence Cells Cultured Brain-derived neurotrophic factor biology Brain-Derived Neurotrophic Factor Biological activity Cell biology Chemistry Nerve growth factor nervous system chemistry biology.protein Neuroscience Neurotrophin |
| Zdroj: | Journal of Neurochemistry. 70:1712-1721 |
| ISSN: | 1471-4159 0022-3042 |
| DOI: | 10.1046/j.1471-4159.1998.70041712.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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