The drug RUC-2 bound to integrin (alpha)IIb(beta)3, as seen in the crystal structure. The drug binds at the interface between the aIIb and (beta)3 subunits.
New Drug Blocks Blood Clotting
A new drug blocks blood clots in heart disease and stroke in a way that may minimize harmful side effects, reports a new study in Science Translational Medicine from Jieqing Zhu, Jianghai Zhu and Timothy Springer at IDI/PCMM and collaborators that include Barry Coller at Rockefeller University. Blood platelets need to stick together to stop people from bleeding when a blood vessel is damaged, but when they stick together at the site of a coronary artery, they can trigger heart attack. Patients typically take clotting inhibitors to prevent platelets from clogging arteries. Platelets glue together when a surface receptor called integrin aIIbβ3 is activated and a bridging molecule in the blood (fibrinogen) simultaneously binds to receptors on two different platelets. RUC-2 prevents the binding of the bridging molecule to the integrin receptor, thus prevent platelets from sticking together.
Zhu, Coller, Springer, and co-workers previously determined a crystal structure of RUC-1 bound to aIIbβ3. They used this information to design a much more potent inhibitor, RUC-2. In a novel twist for an integrin inhibitor, RUC-2 also displaces a key metal ion from the ligand-binding site on the integrin receptor.
RUC-2 targets the aIIbβ3 receptor, just like the other three medications currently on the market, but doesn't cause the receptor to change shape or become activated to the same extent that the others do. The drastic change of shape triggered by other drugs may contribute to harmful side effects like low platelet counts, which can lead to bleeding. Using crystallography techniques and computer simulations, Jieqing Zhu and colleagues show that RUC-2 works by obstructing the binding of a bridging molecule to aIIbβ3, thus keeping sticky platelets apart. However, RUC-2 binds in a different way than other inhibitors, resulting in its lack of activation of shape change by the receptor. The next step is to test whether or not RUC-2 makes a good drug in animals.
Structure-Guided Design of a High-Affinity Platelet Integrin aIIbβ3 Receptor Antagonist That Disrupts Mg2+ Binding to the MIDAS. Zhu J, Choi WS, McCoy JG, Negri A, Zhu J, Naini S, Li J, Shen M, Huang W, Bougie D, Rasmussen M, Aster R, Thomas CJ, Filizola M, Springer TA, Coller BS. Sci Transl Med. 2012 Mar 14;4(125):125ra32.