Thrombosis is a primary cause of death in the US and developed world. Fatal or debilitating blood clots occur in the three major diseases of the western world: heart attacks, stroke and cancer. Two of the major drugs used therapeutically to prevent blood clots are in the top drugs causing serious adverse effects, particularly bleeding, leading to emergency room treatment of patients. Our goal is to develop new antithrombotic drugs that overcome the limitations of current marketed drugs. Our molecular target is the prothrombinase complex. To that end, we will integrate virtual (computer) screening methods and biophysical/biochemical assays to identify lead compounds that can potentially be optimized to produce novel drugs for the treatment of thrombosis. Virtual screening, which requires the availability of atomic resolution 3D structures of the target protein, provides a cost effective way to screen millions of compounds to identify just a few to be purchased and tested in a biological or biochemical assay. Our access to such 3D structures of Factor Xa makes this work possible.
The specific aims of this work are to: 1. Use virtual screening methods to identify compounds that bind in the FXa-Va interface. 2. Determine the binding of compounds selected in Specific Aim 1 to FXa using biophysical assays. 3. Determine inhibitory activity of the selected compounds confirmed in Specific Aim 2 using in vitro assay systems.

Public Health Relevance

Uncontrolled blood clotting or thrombosis is a primary cause of death in the US and developed world. Fatal or debilitating blood clots occur in the three major diseases of the western world: heart attacks, stroke and cancer. The drugs used therapeutically to prevent blood clots have serious adverse effects including bleeding. Our goal is to develop new drugs that overcome the limitations of current marketed drugs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43HL114261-01
Application #
8313509
Study Section
Special Emphasis Panel (ZRG1-VH-F (10))
Program Officer
Pucie, Susan
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$347,218
Indirect Cost
Name
Shifa Biomedical Corporation
Department
Type
DUNS #
192526221
City
Malvern
State
PA
Country
United States
Zip Code
19355