Human iron overload as a consequence of beta-thalassemia, hemochromatosis, or sickle cell anemia is a serious clinical problem. Iron chelation therapy is effective, but the goal of developing readily available, orally-active, effective and non-toxic sequestering agents have proven to be remarkably difficult to achieve. Desferrioxamine (Desferal(r)), a trihydroxamate ligand, remains the iron chelator of clinical use in the United States. Desferal(r) is expensive, has a short half-life in vivo, does not efficiently remove iron from transferrin, must be given on a regular, frequent basis by a subcutaneous or intravenous route, and its use can result in significant, irreversible toxicity. While there are other agents being investigated and developed as potential successors to Desferal(r), there is no established chelator that has yet met this target. The goal of this project is to develop new sequestering agents that would meet that need. In the previous period of support, in collaboration with the Children's Hospital of Oakland Research Institute (CHORI) and Dr. Patricia Durbin- Heavey at the Lawrence Berkeley National Laboratory (LBNL), both new ligand systems and new screening protocols have been developed. The radioactive tracer mouse model at LBNL has been found to be accurate and reliable and has been selected as this project's routine screening protocol. Several promising new multidentate ligands have been developed based on the continuing hypothesis that multidentate, rather than bidentate or tridentate, hydroxypyridonate ligands will be effective as oral chelating agents effective at concentrations below toxic levels. A kinetic animal model has been developed for the metabolism of these agents that accurately fits the observed behavior. It is now proposed to extend these animal studies and to develop the chelators to the point where they can be accepted for large-scale testing, with the ultimate goal being the production of a safe, orally-active iron chelating agent that will prevent the toxicity of iron accumulation in patients who require chronic red cell transfusions. Several new ligand types are proposed with specific hypotheses about structural function relationships. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK057814-06
Application #
6918272
Study Section
Erythrocyte and Leukocyte Biology Study Section (ELB)
Program Officer
Badman, David G
Project Start
2000-06-01
Project End
2008-07-30
Budget Start
2005-08-01
Budget End
2006-07-30
Support Year
6
Fiscal Year
2005
Total Cost
$203,496
Indirect Cost
Name
University of California Berkeley
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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