Reengineered 1,4-dihydropyridines target potassium channel to treat stroke and anemia

What is it about?

1,4-dihydropyridines, highly prescribed medicines (examples amlodipine, nifedipine and felodipine) used to treat high blood pressure and chest pain, block proteins called L-type calcium channels. We used a method called SOSA (selective optimization of a side activity) to reengineer the old 1,4-dihydropyridines into new drugs that potently and specifically block a protein called the KCa3.1 potassium channel. KCa3.1 is widely recognized as a drug target to treat stroke, brain cancer, lung fibrosis, inflammatory bowel disease, hemolytic anemias, and many other disorders. We defined the mechanism of action of one of these drugs, DHP-103, through structural and functional studies.

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Why is it important?

Our proof-of-concept experiments highlighted DHP-103’s potential as a treatment for hereditary xerocytosis, a hemolytic anemia. In a rat model of acute ischemic stroke, DHP-103 substantially reduced infarcted brain damage by dampening neuroinflammation at concentrations that were well tolerated. Future studies in animals and clinical trials in humans are required to establish DHP-103 as a therapeutic for the many diseases related to KCa3.1.