Scientists distinguish new compound that may forestall heart arrhythmia risk from basic drugs

Overview

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• Source: Washington University in St. Louis


• Date: 16 May,2021

Dozens of commonly used drugs, including antibiotics, antinausea and anticancer medications, have a potential side effect of lengthening the electrical event that causes regeneration, creating an irregular heartbeat, or cardiac arrhythmia called acquired Long QT syndrome. While safe in their current dosages, some of these drugs might have a more therapeutic benefit at higher doses, but are limited by the possibility of arrhythmia.

Through the computational and experimental validation, a multi-institutional group of researchers has identified a chemical that prevents the lengthening of the heart’s electrical event, or action potential, resulting in a significant step toward safer use and enlarged therapeutic efficacy of these drugs when taken in conjunction. The group found that the compound, called C28, not only prevents or reverses the negative physiological effects on the action potential, but does not cause any change on the normal action potential when used alone in the same concentrations. The outcomes, found through rational drug design, were published online Friday, May 14 in the Proceedings of the National Academy of Sciences.

The drugs in question, in addition to several that were pulled from the marketplace, cause a prolongation of the QT interval of the heartbeat, known as acquired Long QT Syndrome, that predisposes patients to cardiac arrhythmia and sudden death. In rare cases, Long QT also can be caused by specific mutations in genes that code for ion channel proteins, which conduct the ionic currents to generate the action potential. Although there are several types of ion channels in the heart, a change in at least one of them may lead to this arrhythmia, which leads to approximately 200,000 to 300,000 sudden deaths a year, more than deaths from stroke, lung cancer or breast cancer.

The team selected a specific target, IKs, for this work since it’s one of the two potassium channels that are activated during the action potential: IKr (rapid) and IKs (slow).

“The rapid one plays a significant role in the action potential,” said Cohen, one of the world’s top electrophysiologists. “If you block it, Long QT results, and you get a long action potential.

It was this difference in roles that indicated that increasing IKs may not significantly affect normal electrical activity but could shorten a lengthy action possible.

Cui, an internationally renowned expert on ion channels, and the team wanted to find out if the prolongation of the QT interval could be prevented by compensating for the change in current and inducing the Long QT Syndrome by enhancing IKs.

Zou, an internationally recognized expert who specializes in developing new and efficient algorithms for predicting protein interactions, and the team used the nuclear structure of the KCNQ1 unit of the IKs channel protein to computationally screen a library of a quarter of a million small compounds that targeted this voltage-sensing domain of the KCNQ1 protein device.

To do so, they developed software called MDock to check the interaction of small compounds with a particular protein in silico, or computationally. By identifying the geometric and chemical traits of the tiny compounds, they can get the one that fits into the protein — sort of a high tech, 3D jigsaw puzzle. While it sounds simple, the process is quite complicated as it involves charge interactions, hydrogen bonding and other physicochemical interactions of the protein and the small compound.

One by one, Zou and her lab docked the potential compounds with the protein KCNQ1 and compared the binding energy of each one. They selected about 50 candidates with quite negativetight, binding energies.

Cui and his laboratory then identified C28 using experiments out of the 50 candidates identified in silico by Zou’s lab. They affirmed that the docking results by measuring the change of voltage-dependent activation of the IKs channel at different concentrations of C28 to confirm C28 indeed enhances the IKs channel function. They also studied a series of genetically modified IKs channels to reveal the binding of C28 to the site for the in silico screening.

Cohen and his laboratory tested the C28 compound in ventricular myocytes from a small mammal model that expresses the same IKs channel as humans. They discovered that C28 could stop or reverse the drug-induced prolongation of the electrical signals across the cardiac cell membrane and minimally affected the normal action potentials at the same dosage. They also determined that there were no significant effects on atrial muscle cells, an important control for the drug’s possible use.

“We are very excited about it,” Cohen said. “In many of these medications, there’s a concentration of the drug that’s acceptable, and at higher doses, it becomes dangerous. If C28 can eliminate the danger of inducing Q-T prolongation, then these drugs can be used at higher concentrations, and oftentimes, they can become more therapeutic.”

While the chemical needs additional testing and verification, the researchers say there is enormous potential for this compound or others like it and could help to convert second-line drugs into first-line drugs and reunite others to the market. With the aid of the Washington University Office of Technology Management, they have patented the chemical, and Cui has founded a startup company, VivoCor, to continue to operate on the chemical and others like it as potential drug candidates. The work was hastened by a Management and Entrepreneurial Acceleration Program (LEAP) Inventor Challenge grant Washington University in St. Louis in 2018 financed by the Office of Technology Management, the Institute of Clinical and Translational Sciences, the Center for Drug Discovery, the Center for Research Innovation in Biotechnology, and the Skandalaris Center for Interdisciplinary Innovation and Entrepreneurship.

“This work was done through an effective drug design strategy: identifying a critical site in the ion channel based on comprehension of structure-function relation, using in silico docking to identify compounds that interact with the critical site in the ion channel, validating functional modulation of the ion channel from the compound, and demonstrating therapeutic potential in cardiac myocytes,” Zou said. “Our three labs form a great team, and without any of them, this wouldn’t be possible.”