American and French researchers have isolated the third in a family of three receptors on the surface of platelet cells, which play a critical role in clotting.

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Earlier studies isolated two different platelet receptors, but researchers were convinced a third remained to be identified. While they knew that current anti-platelet drugs likely affected this receptor, researchers could not fully understand how the drugs worked - or maximize their effect - until the final receptor was isolated.

Now, researchers have found the gene for the much-sought-after receptor, called P2Y12. Two drugs that inhibit platelet function, clopidogrel (also known as Plavix) and ticlopidine (Ticlid), were known to target and irreversibly block the third receptor.

"We were very interested in determining what the molecular identity of that receptor was, because it was known to be a validated drug target," says Pamela Conley, a senior scientist at COR Therapeutics, Inc., in South San Francisco, California, USA. Conventional anti-platelet drugs have been effective in treating patients with stroke and peripheral arterial disease, although the medications require roughly 48 hours to take effect.

Conley, senior author of the study, says her company hopes to develop new drugs that would target this receptor, work quickly and effectively, but have a reversible impact. And to do that, they needed a better idea of what this receptor looks like and how it works.

"Now that we have this [genetic information] for this receptor, we can start asking questions about how these known drugs actually interact with the receptor … and hopefully design better drugs," she says.

'A better handle'

Dr. Lawrence Brass, a professor of medicine and pharmacology at the University of Pennsylvania, USA praises the study for identifying the P2Y12 receptor. "By identifying the receptor, it's now possible to get a better handle on why those drugs work," he says. "And since those drugs have been occasionally associated with an unacceptable toxicity, it really opens the door for designing drugs that will have the same benefit, but hopefully not with the same toxicity."

Brass specifically referred to thrombotic thrombocytopenic purpura (TTP), a clotting disorder that can lead to kidney failure, stroke, heart attack, even death. TTP, while very rare, has been linked to the drugs Plavix and Ticlid.

Conley says she is encouraged by the fact that the P2Y12 receptor seems to be distributed only in certain body tissues. This makes it much less likely that a drug that targets P2Y12 would have undesirable side effects, she says.

"The only other place that we know this receptor is expressed, based on our studies, is in the brain, " says Conley. "If you had to had to have a receptor expressed in a second place, that's really the best place, because there's a blood-brain barrier that exists that protects the brain, and many drugs are not capable of crossing that blood-brain barrier."

Conley's next step will be to breed a strain of mice that lack the P2Y12 gene and study their platelets and response to vascular injuries. This also will give the researchers a tool with which to design better drugs.

The Heart and Stroke Foundation South Africa
 

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