The human heart pumps blood through the body and beats rhythmically through a complex system of electrical activity. A disruption in the timing of that activity can cause a whole cascade of adverse effects, including sudden death in patients with Long QT syndrome.
Jianmin Cui, professor of biomedical engineering in the School of Engineering & Applied Science at Washington University in St. Louis, is taking an innovative approach to finding new drug candidates to treat this syndrome with a four-year, $3.1 million grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health. This work will build on Cui's ongoing research into the molecular bases behind the causes of Long QT syndrome, arrhythmia, or irregular heartbeat, and other cardiac disorders.
Long QT syndrome, which causes arrhythmia, can be inherited or acquired after use of certain medications and is caused by specific mutations in genes that produce ion channels, which provide the current for the heart's electrical activity. Although there are several types of ion channels in the heart, a change in one or more of them may lead to arrhythmia.
In addition, some patients may acquire Long QT syndrome as a side effect of taking certain common medications, resulting in some compounds being pulled from the market that could have treated other diseases.
Over the course of the study, Cui and his team will determine if compensating for the change in current from any of the channels by substituting a balancing current from a different one will lead to restoring normal function and rhythm. Specifically, they will use structural information about how the potassium ion channel IKs is activated to perform computer-based drug screening to look for compounds most likely to interact with the IKs channel. Using innovative computer algorithms that they design, they will screen for these compounds in a database of 1,500 U.S. Food & Drug Administration-approved, small-molecule drugs. Any promising compounds will then be tested in cardiac cells to determine their effects on the currents in heart tissue, both normal and with Long QT syndrome.
"This new paradigm will help ion channel-targeting drug discovery to be 'faster, cheaper and safer,'" Cui says. "If any of these drugs works to enhance the potassium ion channel, it should eliminate some safety barriers for FDA approval."
Cui says the study has more broad implications as well.
"If successful, this approach can point the way in defining how a combination of experimental studies and computer simulations can lead to rational drug development for other ion channel diseases," he said.
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