March 12, 2014
Heart Attack Patients May Soon Have Side Effect-Free Drug Option
April Flowers for redOrbit.com - Your Universe Online
A new drug designed to stop a heart attack in its tracks, while reducing the damage caused, all without side effects, is one step closer to development thanks to a group of Melbourne scientists from Monash University.
A team of scientists, led by Professors Arthur Christopoulos and Peter Scammells from the Monash Institute of Pharmaceuticals Sciences (MIPS), combined molecular pharmacology and medicinal chemistry to reveal new insights into a specific protein belonging to the family of G protein-coupled receptors (GPCRs). Combining two of the molecules successfully allowed the team to move one step closer to creating targeted drugs that could possess minimal side effects.
In nearly every biological process, GPCRs play a role. This is also true for most diseases, including, cardiovascular disease, obesity and diabetes, neuropsychiatric disorder, inflammation and cancer. The therapeutic effect of nearly half the medications currently available is achieved through the use of GPCRs.
The currently available drugs that use GPCRs work either by fully activating, or completely blocking receptors. In this way, they treat the protein like a simple "on-off" switch. Alternative recognition sites on GPCRs, that can be targeted by drugs to fine-tune the behavior of the protein rather than just switching it on and off, has been discovered by the new team of researchers. This targeted approach turns the "on-off" switch into a "dimmer" switch.
It was this insight, according to Christopoulos, that enabled the new breakthrough.
“When a heart attack strikes, heart cells die because of a lack of oxygen and nutrients. But even more damage is caused when the blood rushes back to the heart cells due to the release of inflammatory chemicals and damaging free radicals,” Professor Christopoulos said.
Drug therapies currently used to minimize heart damage activate the adenosine A1 receptor, a GPCR found in the heart. Activating the A1 receptor also slows down the heart, however, meaning that activating it too much could stop the heart.
“Correct dosage has been a serious challenge in clinical trials for A1 receptor drugs. 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,” Professor Scammells said.
Scammells and Christopoulos focused their study on finding new ways to activate the protein, in order to achieve the beneficial effects (protection) without the side effects (slowing the heart).
“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. Our “dimmer switch” strategy worked, resulting in a molecule that protected heart cells but did not affect heart rate at all – at least in our animal models," Professor Christopoulos said.
"The beauty of this protein is that if you activate it effectively, you minimise the heart attack and protect the heart cells, and that’s something that’s never been done before."
The next research phase for the team will be to develop a new drug that could possibly be made available for use by clinicians and emergency paramedics.