Computer assisted molecular design and combinatorial approaches will be used to prepare agonists/antagonist of the nerve growth factor. This work is to understand TrkA/NGF receptor-ligand interactions and to aid development of new pharmaceuticals for treatment of neurodegenerative diseases and cancer. To do this, four new scaffolds will be tested as a means to hold sequences of 2, 3, 4, of 6 amino acids into turn arrangements, specifically those sequences and conformations that correspond to critical loop regions of NGF. Syntheses of libraries of peptidomimetics require efficient routes that ideally do not involve chromatographic separations. Consequently, the proposed NGF-mimic preparations feature reactions in which formation of the caffold and cyclization occur simultaneously via steps which are known to be highly efficient, such as displacements of benzylic halides with thiolates. The monovalent products (having only one turn) are expected to be TrkA antagonists. To target potential agonists, a unique strategy of reactions of libraries with libraries will be applied to tether pairs of the monovalent compounds to form bivalent mimics. The latter are intended to induce receptor dimerization. Functional TrkA binders will be identified and examined via tests to probe conformation, function in vivo, receptor binding, effects on cell metabolism (via cytosensor microphysiometry), function in vitro, signal transduction, dose/receptor in cell survival assays, and finally preclinical therapeutics trials. Structure/activity/conformation data thereby collected will be used to design and prepare small molecule derivatives of these peptidomimetics.
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