Neuropharmacology of Conophans and Hydroxyconophans This AREA project proposal is aimed at the isolations and functional characterization of conophans and ?-hydroxyconphans, two new classes of related conopeptides discovered in our laboratory, whose trademark is a D-Xaa-Trp motif near the C-terminal (Conophans) and the unexpected ?-hydroxylation of the D-amino acid of this motif (?- hydroxyconophans). These compounds were isolated from the venom of several cone snail species (C. gladiator, C. mus and C. villepinii, so far). Components of the venom of cone snails elicit a wide range of neurophysiological responses and show great potential as therapeutic agents. The biochemical diversity of the venom is part of a neurochemical strategy used by these animals to compete favorably for prey in the marine environment. Conophans and ?-hydroxyconophans add molecular to further diversity this strategy and are of particular interest as they are linear peptides and among the smallest conopeptides isolated to date. The contribution of this project will be to investigate the neuropharmacology of a new class of potential therapeutic agents. This is to be done in an environment that will train students and staff in a multidisciplinary project that ranges from marine science to rational drug discovery and as part of the development of the PI's research program. Conophans and hydroxyconophans can provide a novel set of neuronal probes or pharmacological agents with unique favorable medicinal properties that can be conveniently synthesized. Specifically, we propose to accomplish the following goals: 1) expansion of the current library of existing conophans and ?-hydroxyconophans by chemically screening the venom C. stimpsoni, C. arangoi, C. delesertii and C. lindae. 2) Chemically synthesis the conophans discovered using Fmoc-based solid phase methods 3) To synthesize ?- hydroxyconophans gld-V*/ gld-V*' and mus-V*/ mus-V*' using solid-phase methods. 4) In vitro functional screening of the ?-hydroxyconophans and the conophans to evaluate their neuromodulatory effects and in favorable cases, define their specific neuronal receptor 5) Compilation of a conophans/?-hydroxyconophan library that can serve as novel drugs leads and as probes for neurobiology applications. Conopeptides are powerful neuropharmacological agents that can be used for wide variety of applications. Our laboratory has found a new class of conopeptides that we have named conophans/?-hydroxyconophans. This discovery represents a landmark in peptide and protein biochemistry as these compounds provide the very first examples ?- hydroxylated modifications of the amino acid Valine. We are uniquely poised to explore this great potential for """"""""Drug discovery"""""""" as we posses nanomolar quantities of the only existing library ?-hydroxyconophans. Our goal is to augment our current supply of conophans/?-hydroxyconophans in order to carry out extensive biological assays geared towards the evaluation of these new compounds as potential as therapeutic agents. ? ? ?
