Kir Channel Modulators
Inventors: Scott Pegan, Paul Slesinger, Senyon Choe, Prafulla Aryal
Potential Uses: Cardiology, CNS, Screening, Drug Discovery
Methods and materials for modulating Kir channel activity and identification of related compounds.
Inwardly-rectifying potassium (Kir) channel proteins are involved in a diverse range of biological processes, including regulation of cardiac and neurological functions. In contrast to voltage-gated potassium channels that allow large fluxes of K+ ions out of the cell when opened during membrane electrical activity, Kir channels allow fluxes of K+ ions out of the cell at resting membrane potentials, maintaining excitability. In addition, Kir channels are modulated by alcohols.
Aberrant activity of Kir channels has been linked to a variety of endocrine, cardiac, and neurological disorders. In particular, mutations in Kir channel proteins have been implicated in analgesia, cardiac arrhythmias and Andersen's Syndrome. Consequently, new compounds discovered using the methods described could be therapeutically useful to control heart dysfunctions and neurological disorders such as epilepsy, as well as for developing novel analgesics.
Scientists at the Salk Institute have recently determined the structure of the cytoplasmic domain of the Kir2 channel protein, and discovered that a small alcohol-like molecule, known as MPD, binds to a specific location within the protein domain. Additional studies indicate that low concentrations of MPD activate the related Kir3 subfamily of channel proteins. The Kir channel three-dimensional structure has been used to design mutants for characterizing the pharmacological properties of the alcohol pocket.
This discovery provides a stereochemical basis for the systematic design, synthesis, and screening of related alcohol-like compounds in order to identify those that modulate Kir channel activities. The technology disclosed in the pending patent includes the elucidated structure of a representative Kir channel protein in combination with an alcohol and methods for identifying agents that modulate Kir channel activity and predicting whether an agent is capable of binding to a Kir channel.
Patent Status: U.S. Patent Application published as 2009/0148861 A1
Publications: Nature Neuro. 2009
Biochemistry. 46: 5315-5322 (2007)
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