In the perilous moments after a heart attack, time is rarely on the victim’s side. But thanks to a recent discovery by scientists at Australia’s Monash University, a new heart attack drug that’s capable of minimizing the overall damage quickly, could be in the mix.
Myocardial infarction — more commonly known as a heart attack — involves the massive and rapid death of heart cells, which have stopped receiving oxygen and nutrients because of a block in the person’s arteries. But the real damage, the researchers assert, occurs when the blood rushes back into the heart due to the release of inflammatory chemicals and free radicals. Ultimately, if they could develop a drug that stops that second rush, the chances of survival would skyrocket.
Current drugs target what’s known as the adenosine A1 receptor. It’s part of a family of receptors known as G protein-coupled receptors, or GPCR. The A1 receptor is responsible for a number of things, including sleep regulation, and has a depressant effect on the heart’s smooth muscle when activated. The trick in developing drugs is finding the appropriate activation level.
“Correct dosage has been a serious challenge in clinical trials for A1 receptor drugs,” co-researcher Professor Peter Scammells from the Monash Institute of Pharmaceutical Sciences, said in a statement. “The consequences are serious; a dosage that is too high can stop the heart from beating. Too low, and the drug fails to prevent cell damage. Getting this balance right has been a big problem.”
Heart attack is recognized as one of the leading causes of death in the U.S. Heart disease more broadly accounts for one in four deaths, or roughly 600,000 total deaths, each year. It is the leading cause of death in both men and women. Roughly 715,000 Americans have a heart attack each year.
Scammells and his colleague, Professor Arthur Christopoulos, sought to solve this problem in their latest study, forthcoming in Proceedings of the National Academy of Sciences. They realized that many GPCR drugs treat the proteins as incapable of sliding between regulatory states. In other words, the drugs turn the receptors into an “on-off” switch. Avoiding that binary state meant taking an alternative path to the A1 receptor.
“We turned to our knowledge of alternative recognition sites on the A1 receptor and specifically designed a new class of molecule that contained two active components linked together, one binding to the main site on the receptor for activation, and another binding to the alternative site for fine-tuning of the activity,” Christopoulos said.
The end result? A “dimmer switch” the researchers could use to slide activation between both extremes. According to Christopoulos, the analysis ended “in a molecule that protected heart cells but did not affect heart rate at all — at least in our animal models.” If the drug achieves parallel results in human models, it would mean the dimmer switch successfully, and safely, controls the activation of the A1 receptor, preventing dangerous chemicals from flooding the heart but keeping the heart awake enough that it can pump.
Ideally, the findings will take the research to pharmacological development, putting the drug at the disposal of emergency paramedics and clinicians. "The beauty of this protein is that if you activate it effectively, you minimize the heart attack and protect the heart cells,” Christopoulos said, “and that’s something that’s never been done before."