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An image of the enzyme that is targeted by the
sulfated DHPs, the new molecules designed by Desai�s team. The new
molecules bind to thrombin (exosite II).
The structure of a typical sulfated DHP.
Images courtesy of Umesh R. Desai, Ph.D./VCU.
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In a study published in the Nov. 2 issue of
the Journal of Biological Chemistry, Umesh R. Desai, Ph.D., a
professor in the Department of Medicinal Chemistry at the VCU School
of Pharmacy, lead investigator on the study, reported on the design of
three highly complex molecules with unique anticoagulant properties
that were prepared in the laboratory. According Desai, these molecules,
known as sulfated DHPs, are completely different from anticoagulants
used in the clinic today including heparins, coumarins and hirudins.
The team demonstrated that the molecules were able to inhibit the
ability of critical enzymes involved with the cascade of events
involved in blood clotting. Specifically, the molecules prevent the
normal action of thrombin and factor Xa, which are the critical
enzymes targeted by current anticoagulant therapy.
"We have identified a new mechanism that may prevent clotting. This
approach may result in new drugs for the treatment of thrombotic
disorders, including pulmonary embolism, deep vein thrombosis and more,"
said Desai.
"The molecules we have designed may possess several advantages
compared to currently available anticoagulation drugs," he said.
"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."
Desai and his team are now investigating which unit or units in the
complex molecule are responsible for the anti-clotting activity.
This work was supported by grants from the National Institutes of
Health and the American Heart Association National Center.
Desai collaborated with VCU researchers Brian L. Henry, Bernhard H.
Monien; and Paul E. Bock, who is affiliated with Vanderbilt
University.
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