Aakancha Shaw, St. Xavier’s College, Kolkata
There are many such drugs Or rather commonly used drugs that include various types of antibiotics, antinausea and anticancer medications, that have a potential side effect of lengthening Or increasing the electrical event that leads to systole(contraction), thus creating an irregular heartbeat which is known as cardiac arrhythmia called acquired Long QT syndrome. Although these are safe in their prescribed dosages, some of these drugs might have a more therapeutic benefit at higher doses, but their use has been limited due to the risk of arrhythmia: Irregular heartbeat.
After extensive research to prevent this from happening, researchers identified a compound that can prevent the lengthening of the heart’s electrical event or action potential. This discovery can lead to a major step toward safer use and expanded therapeutic efficacy and the advantage of these medications can be derived. The team found that the compound, called C28 could not only prevent or reverse the negative physiological effects on the action potential but also does not cause any significant change when used alone at the same concentration on the normal action potential. Various types of drugs have been identified in the market that is known to cause a prolongation of the QT interval of the heartbeat. This is known as acquired Long QT Syndrome, which predisposes patients to cardiac arrhythmia and then sudden death. In extremely rare cases, Long QT can be caused by specific mutations in genes that generally code for ion channel proteins, which conduct the ionic currents to generate an action potential. Although there are several different types of ion channels in the heart, a change in even one or more of them may lead to this arrhythmia, which contributes to about 2lakhto 3 lakh sudden deaths in a year, which is more than the deaths caused by stroke, lung cancer or breast cancer.
The research team selected a specific target, IKs, for this work because it is either one of the two potassium channels that are activated during the action potential: IKr (rapid) and IKs (slow).IKr(rapid) plays a major role in the action potential. If IKris blocked, Long QT results and a long action potential is generated. IKs is very slow relatively and hence contributes much less to the normal action potential duration. It was due to this difference in roles that suggested that possibly increasing IKs might not significantly affect normal electrical activity but could shorten a prolonged action potential. Also, the prolongation of the QT interval could be somehow prevented by compensating for the change in current by enhancing the IKs(slow)- it induced the Long QT Syndrome. The scientists also discovered a site on the voltage-sensing domain of the IKs potassium ion channel that could be easily accessed by small molecules.
The scientists were able to develop a software called MDock. MDock was developed to test the interaction of small compounds with a specific protein computationally. By identifying the chemical and geometric traits of the small compounds, they can identify the compound that fits into the protein. Researchers then identified C28 using this method. Again, they validated the docking results by measuring the shift of voltage-dependent activation of the IKs channel at different concentrations of C28 to conclude that C28 indeed enhances the IKs channel function. And, the result of the numerous experiments was that if C28 can eliminate the danger of inducing Q-T prolongation, then these drugs can be used at higher concentrations, and in many cases, they can become even more therapeutic.
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