New Synthetic Molecules Possess Anti-Clotting Properties

A novel study describes a mechanism to inhibit key enzymes that occupy a major role in clotting disorders, which could lead to innovative therapies to treat blood clots in inaccessible areas such as the lungs and deep veins.

Researchers at Virginia Commonwealth University (Richmond, USA) developed three highly complex molecules with unique anticoagulant properties. The molecules, sulfated dehydropolymers (DHPs) of 4-hydroxycinnamic acids, were able to inhibit the ability of critical enzymes involved with the cascade of events involved in blood clotting. All three sulfated DHPs displayed a 2-3-fold preference for direct inhibition of thrombin over factor Xa--which are the critical enzymes targeted by current anticoagulant therapy--whereas the preference for inhibiting thrombin over factor IXa and factor VIIa increased to 17-300-fold, suggesting a high level of selectivity.

The designed sulfated DHPs appear to bind primarily in the region defined by exosite II, allosterically preventing the normal action of thrombin and factor Xa. The researchers stress that the new molecules are completely different from standard anticoagulants used in the clinic today including heparins, coumarins, and hirudins, which may cause some patients to develop adverse reactions to the therapy. The study was published in the November 2, 2007, issue of the Journal of Biological Chemistry.

"The molecules we have designed may possess several advantages compared to currently available anticoagulation drugs,” said lead author Umesh R. Desai, Ph.D., of the department of medicinal chemistry and the institute for structural biology and drug discovery. "For example, new anti-clotting therapies may result in reduced hospital stays for patients, fewer side effects, and possibly an overall cost reduction in therapy because our molecules are likely to be synthesized in an inexpensive manner.”


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