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. Two of the major drugs used therapeutically to prevent blood clots are in the top drugs causing serious adverse effects leading to emergency room treatment of patients. Our goal is to develop new anti- thrombotic drugs that overcome the limitations of current marketed drugs. Our molecular target is Factor XIa (FXIa), a serine protease that plays a key role in the amplification of the blood coagulation cascade. To that end, we will integrate virtual (computer) screening methods and 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 million 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 the FXIa catalytic domain makes this work possible.
The specific aims of this work are to: 1. Use virtual screening methods to identify compounds that bind in the FXIa active site. 2. Determine the ability of the selected compounds to inhibit FXIa activity in an in vitro assay. 3. Confirm the activity of the selected compounds determined in Specific Aim 2 using plasma or blood-based 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. Two of the major drugs used therapeutically to prevent blood clots are in the top drugs causing serious adverse effects leading to emergency room treatment of patients. 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 #
1R43HL092680-01
Application #
7481477
Study Section
Special Emphasis Panel (ZRG1-HEME-D (10))
Program Officer
Link, Rebecca P
Project Start
2008-04-15
Project End
2010-04-14
Budget Start
2008-04-15
Budget End
2010-04-14
Support Year
1
Fiscal Year
2008
Total Cost
$256,345
Indirect Cost
Name
Shifa Biomedical Corporation
Department
Type
DUNS #
192526221
City
Malvern
State
PA
Country
United States
Zip Code
19355