Methods and Reagents for Screening New Drugs and Treating Ion Pump Associated Disorders
Background: Sodium/potassium ATPases (Na+/K+-ATPases), a family of multi-subunit ion pumps, are the most important active transporters in animal cells. They are required for maintaining the electrochemical gradient responsible for resting membrane potentials in neuronal cells and for the function of other transport proteins in a variety of cell types. The important regulatory activities of Na+/K+-ATPases make them an attractive therapeutic target for the treatment of neurodegenerative, cardiac, and other diseases. To date, there are unmet medical needs for the treatment of these diseases, and it is desirable to discover and develop novel therapeutic agents aimed at treating ion pump related disorders. Technology: Researchers at the University of California have discovered that agrin, a naturally occurring ~400 kDa extracellular matrix protein, binds specifically to one member of the Na+/K+-ATPase family and inhibits its activity. Two minimal fragments of agrin were discovered; one that acts as an agrin antagonist and one that binds and modulates the Na+/K+-ATPase 3 subunit. Agrin fragments, which can have agonistic or antagonistic activity, can be used as a tool to differentiate between different members of the Na+/K+-ATPase family. Exploiting the binding specificity of agrin fragments forms the basis for a new methodology to screen drug candidates for the treatment of ion pump associated disorders. Novel drug candidates can be assayed for their ability to block binding of an agrin fragment and/or screened for their ability to bind other members of the Na+/K+-ATPase family. Using this methodology, for example, cardiac glycoside drug candidates can be identified for their potential to treat congestive heart failure while having reduced or no neurological side effects. Application: The methodology described in this invention is ideally suited for screening and identifying biologically active drug candidates directed against specific Na+/K+-ATPases. Such drug candidates can potentially be useful for treatment of (i) neurological diseases including epilepsy, seizures, Alzheimer's disease, and Parkinson disease, (ii) cardiac diseases including congestive heart failure and hypertension, and (iii) other ion pump associated disorders.
The University of California seeks to develop and commercialize this invention via a license agreement and/or by performing sponsored research in collaboration with a company.
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