On the Pulse: New Drug Linked to Potentially Toxic Effects

Mary Kudaibergenova, PhD candidate at the University of Calgary, has been fascinated by health and science throughout her academic journey. Motivated by her own personal experiences with healthcare and medicine, Mary’s interest in the field continued throughout high school, her undergraduate degree in Biological Sciences at the University of Calgary, and her current studies.

Unanswered questions, or “mysteries and puzzles” as Mary describes, have always sparked her curiosity. When she took a course offered by Dr. Sergei Noskov, she was captivated by the enigmatic world of structural biology. Mary notes that the significance and global impact of drug design, clinical trials, and research in the field are an inspiring and fulfilling part of her graduate work.

Mary has worked alongside University of Calgary Professor and Associate Head (Research) in Biological Sciences, Dr. Noskov, and research team comprised of investigators from the Faculty of Science and Cumming School of Medicine. The team has recently published an article in the journal ‘Molecular Pharmacology’ detailing their discovery of the toxic effects of Ivabradine, a new drug intended to lower an individual’s heart rate.

Ivabradine was approved by the American Food and Drug Administration (FDA) in 2015 and has since been prescribed widely in North America. Prior to 2015, Ivabradine (more commonly known as Corlanor) was available in Europe and prescribed to allow for more efficient blood flow to vital organs throughout the body.

Drug toxicity is a problem that can have serious implications in our society, especially impacting vulnerable populations such as children, the elderly, or those who are immuno-compromised. It is often difficult to diagnose drug toxicity in its early stages. Dr. Noskov and Kudaibergenova explain that there are two main sources of drug toxicity: lung and cardiac. They note that drugs have the potential to bind somewhere else in the body as it is it passes through the circulatory system. Most recreational drugs, such as fentanyl or commonly prescribed medications ranging from antibiotics to anti-anxiolytics, can bind to cells in other regions in the body instead of the main target cell.

For example, an antidepressant’s main target is in a specific area of the brain, but there is potential for an antidepressant to bind elsewhere, like the heart. They describe that when a drug binds within the heart, negative effects such as Long QT Syndrome (an arrhythmia of the heart) may occur. In some cases, this “promiscuous binding” of variously chemically diverse drugs may lead to a drug-induced heart failure, one of the most common fatalities related to the drug toxicity. Unfortunately, ~ 90% of potentially life-saving medications do not make it to the public due to cardiovascular toxicity, and many patients suffer from adverse side effects of drugs during pre-clinical studies.

Dr. Noskov explains that the experimentation and level of analysis needed for clinical trials is complex and costly to the pharmaceutical industry, especially when factored in with the treatment of ailments linked to the adverse side effects of drugs.

In the instance when a drug goes off-target to the heart, the drug blocks ion channels that are crucial in generating and propagating an electrical signal throughout the heart. Like the cork-in the-bottle analogy, when the ion channels (bottle) are blocked by drugs (cork), ions such as sodium and potassium can no longer flow between cells, stopping the normal propagation of the electrical impulse through the heart. This in turn can result in cardiac irregularities such as atrial fibrillation, or a potentially fatal Toursades de Pointes (TdP). Mary describes another finding about Ivabradine, the “used dependent effect - the more you use it, the more likely you will have negative side effects. Likely, Ivabradine accumulates in the cell membrane and blocks the cardiac channel through that path.”

Dr. Noskov and Mary have worked with Dr. Henry Duff laboratories with contributions made equally by Dr. Perissinotti and Dr. Guo. The team has worked for the last two years to develop a more rounded understanding as to what makes drugs like Ivabradine bind to cardiac channels and why. They have examined the properties of Ivabradine in order to better understand different compounds and why such problematic interferences to the cardiac system can occur. Dr. Noskov describes that “by using super computers to understand how proteins live and behave in cellular membranes, ion channels, and secondary transporters, we have been able to study how these compounds participate in the formation of the ‘action potential’ that makes the heart beat.”

The collaboration with Foothills Hospital Electrophysiology Specialist, Dr. Henry Duff (who is also Kudaibergenova’s co-supervisor) was crucial for their breakthrough in this field of research. Dr. Duff has conducted the experimental component of the study and has tested cellular models in order to obtain data to test the predictions made by the Noskov lab.

The application of this research is far-reaching, as various drugs can block ion channels in the heart, including anti-depressant, anti-convulsant, antibiotic, and antifungal medications. Dr. Noskov and Mary discuss that by understanding the chemical compounds that block the cardiac channel, it is possible to understand how to prevent this issue or in some cases, block the channel when advantageous to do so. Dr. Noskov,

Speaking about her experience at the University of Calgary, Mary recounts the positivity and support she has received from both of her supervisors. She envisions herself in research and aspires to complete a Doctor of Medicine (MD) degree to continue research in clinical settings. To prospective PhD candidates and those who wish to pursue a career in the Biological Sciences field, Mary recommends finding an area of interest and maintaining a critical outlook. Mary comments that the journey “is hard work, but is worth it and I think you’ll gain a lot, both personally and professionally.”

The novel discoveries made by the team have already sparked conversation within the scientific community. With findings published, more exciting developments are sure to be uncovered in the Biological Sciences.

For more on Dr. Noskov’s lab, visit: https://www.ucalgary.ca/noskovlab/research

To access the publication “The Pore-Lipid Interface: Role of Amino Acid Determinants of Lipophilic Access by Ivabradine to the hERG1 Pore Domain”, visit: http://molpharm.aspetjournals.org/content/early/2019/06/10/mol.118.115642

Article by Heather Tompson