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Category:Software companies of the United StatesSalty old molecules, like the brain, contain sodium channels, potassium channels and other proteins that maintain the network-like organization of neurons and the inter-relationship between them. Mutations in a single channel protein, NaV1.7, have been linked to a number of neurological disorders including pain, dystonia and epilepsy. Recently, much progress has been made in the development of selective blockers of NaV1.7. Examples include the small molecule Ziconotide, and others that contain two separate pharmacophoric moieties, one for binding to the receptor channel and another for blocking the channel at the cellular level. Although blockers of this type show selectivity, it is clear that their clinical usefulness will be limited, because of their low potency. We propose to explore new structural features that can be used to develop additional selective blockers. Aim 1. Develop a broad-spectrum, nonpeptide inhibitor of NaV1.7. A nonpeptide that binds to the S3-S4 linker of NaV1.7 to block the channel pore will be developed by employing a combination of computer modeling, mutagenesis, and high throughput screening of compound libraries. The ultimate goal of this project is to identify a nonpeptide, broad-spectrum blocker that is selective for NaV1.7 over other NaV channels and Nav channels that are not co-expressed in pain fibers. Aim 2. Identify the allosteric site of action of Ziconotide. The allosteric site of action of Ziconotide is a known target of small molecule blockers and has been shown to be a drug target for Ziconotide itself. We propose to identify the allosteric site of action of Ziconotide by employing a combination of molecular modeling, mutagenesis, and electrophysiology. This work will lead to a greater understanding of the mechanism of action of Ziconotide. Aim 3. Develop additional blockers of NaV1 be359ba680
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