New Molecule Could Lead to Oral Anti-Heart Attack Drug

Imagine: a pill that could dissolve clots that clog blood vessels and cause a heart attack! A pill that could be kept in the medicine cabinet and taken by high-risk patients at the first sign of chest pain, saving precious time and preventing excess damage. New research by Rockefeller University scientists suggests that a new molecule called RUC-1 may be the key to such a pill.

When the body sustains an injury, platelets rush to the site and stick together to help prevent excessive bleeding. However, in a narrow artery with atherosclerosis, they can form a dangerous clot, which can cause permanent damage or even death if it isn’t dissolved or rapidly removed. There are medications called αIIbβ3 inhibitors available that can prevent the platelets from sticking together, but not only must they be administered intravenously, they also have side effects and risks. Barry Coller, Professor David Rockefeller, head of the Allen and Frances Adler Laboratory of Blood and Vascular Biology, and laboratory manager Robert Blue found RUC-1, which not only appears to sidestep the problems with existing drugs, but could be taken orally.

The αIIbβ3 receptor is on the platelets’ surface that is intimately involved in the accumulation process. Interfering with αIIbβ3 can prevent an unwanted clot or “thrombus.” The αIIbβ3 receptor is made up of two halves: the αIIb subunit and the β3 subunit. Previous attempts to create αIIbβ3 inhibitors that could be taken orally led to drugs that bind to both halves; this blocks other platelets from attaching, but also changes the configuration of the receptor to its “on” position. Once the drug wears off, the inhibitor may leave the receptor in the on position, making the platelet primed and ready for other passing platelets to bind. “As a result, once the inhibitor is gone and the receptors are still in the active conformation, you get a paradoxical increase in thrombus formation,” Blue says.

RUC-1 was discovered by screening more than 33,000 compounds. In their research, published in Blood, Coller, Blue and colleagues Marketa Jirouskova and Marta Murcia describe its structural effects. Rather than binding to the entire receptor, RUC-1 binds to only half of it, the αIIb subunit, presumably leaving the other half in the off position. In a separate study, in collaboration with the Children’s Hospital of Philadelphia, Coller and Blue are now assessing the effect of RUC-1 on mice with human αIIb and mouse β3 receptors.

Research assistant Amanda Harrington is now working to synthesize more potent derivatives of the molecule. Meanwhile, the scientists are screening the 250,000 compounds in the NIH Small Molecule Repository using the robotic systems at Columbia University to search for molecules that could be even more effective than RUC-1. “RUC-1 could provide advantages over the currently available inhibitors,” Blue says. “If someone was at very high risk for having a heart attack, he could keep the drug on hand and take it the same way doctors currently suggest using aspirin, swallowing the pill at the first sign of chest pain. This would be the same idea, only much more potent.”