STRUCTURE-ACTIVITY-RELATIONSHIPS OF CONFORMATIONALLY CONSTRAINED PEPTIDE ANALOGS OF LOOP-2 OF BRAIN-DERIVED NEUROTROPHIC FACTOR

Brain-derived neurotrophic factor (BDNF) promotes the survival of vari ous neuronal populations and thus shows potential in the treatment of neurodegenerative disease. However, BDNF is not pharmacokinetically op timal 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 t he three-dimensional structure of BDNF derived by homology modeling as a template. When tested in cultures of embryonic chick sensory neuron s the pep tides produced concentration-dependent inhibition of BDNF-me diated neuronal survival and caused both a rightward shift and depress ion of the maximum of the BDNF concentration-response curve. The compo unds had no effect on the survival response to nerve growth factor and were without intrinsic trophic or toxic effects when added to culture s alone, With the aid of pharmacodynamic simulations we demonstrated t hat the inhibitory activity of the active peptides is consistent with them acting as competitive antagonists of BDNF for its high-affinity r eceptor, trkB. An alanine scan of the largest peptide identified sever al residues important in mediating the inhibitory action of the peptid es, We intend to use the data from these studies to develop small pept idic BDNF-like agonists.