Several weeks ago cardiologists representing 72 organizations from all over the world announced that a new drug called tirofiban -- also known as aggrastat -- could reduce the risk of death in unstable angina patients by 47%. The drug attaches to and blocks biochemical doorways on platelet cells called IIb/IIIa receptors. When bound to these receptors, the drug keeps fibrinogen -- a protein found in the blood -- from adhering to platelets, thereby preventing the formation of platelet thrombi, which can cause arterial blockage.
The lab of Joel Bennett, MD, a professor of medicine, has been working on the molecular biology of the IIb/IIIa receptor for the last 20 years. His lab's discovery of the receptor, its amino acid sequence, and how it works in conjunction with proteins like fibrinogen laid the groundwork for these recent clinical advances. In the last year, Bennett and colleagues have been trying to find out how IIb/IIIa gets activated in the first place. Platelets -- via the IIb/IIIa receptor -- remain inactive until needed.
"So now we're studying the way in which IIb/IIIa goes from an inactive state to an active one to eventually figure out how to inhibit platelet aggregation," says Bennett. "Clinically, any drug that would come out of this would be used in the same way as tirofiban, but may have the potential to be more potent in its anti-thrombotic characteristics."
But here's the rub: To
study how IIb/IIIa gets activated presents a challenge because platelets are one
of the only cells in the body that don't have nuclei, thereby useless for
studies in which genetic manipulation of a protein is necessary. In a paper in
the June 12 issue of the Journal of Biological Chemistry, Bennett's team
describes a new technique in which they have successfully changed and
experimented with IIb/IIIa receptors expressed in b-lymphocytes, circumventing
the platelet problem. This is the first step in making the necessary discoveries
for the next generation o
'"/>
Contact: Karen Young Kreeger
kreeger@mail.med.upenn.edu
215-662-2560
University of Pennsylvania School of Medicine
29-Jun-1998