The specific goal of the proposed project is to accelerate the overall development of desferrithiocin based chelating agents for decorporation of radionuclides. Past systematic structure-activity studies have allowed the design and synthesis of analogues and derivatives which retain the exceptional iron-chelating activity of desferrithiocin (DFT) while eliminating its adverse effects. The hypothesis underlying the research program is that a similar approach can be adopted to utilize the DFT platform for the design of ligands that will effectively decorporate actinides. On the basis of past experience, the results of extensive studies of iron chelation in rodents and primates, and a wide-ranging review of the available scientific literature, a ligand basis set which includes a number of chelators already shown to decorporate uranium was selected to represent the best available candidates at present for the decorporation of U(Vl), Th(IV) [a surrogate for Pu(lV)] and Eu(lll) [a surrogate for Am(lll)J. Systematic investigations in rodents (including dose-response, pharmacologic, toxicologic and histopathologic studies) will identify the DFT chelators in the ligand basis set that are most effective and least toxic for decorporation of U(Vl), Th(IV) and Eu(lll). An innovative new approach using MRI to characterize the action of a selected chelator on distribution and elimination of Eu (lll) in rodents will also be examined. Ultimately, the most promising candidate chelators will be evaluated in a primate model to provide the best available evidence for efficacy in humans. ? Accordingly, the proposed research will identify the lead DFT chelator(s) to enter further product development and provide critical data for the design of studies to prospectively assess efficacy in animals and safety in humans. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI074068-01
Application #
7267878
Study Section
Special Emphasis Panel (ZAI1-KLW-I (S4))
Program Officer
Maidment, Bert W
Project Start
2006-09-15
Project End
2009-09-30
Budget Start
2006-09-15
Budget End
2009-09-30
Support Year
1
Fiscal Year
2006
Total Cost
$1,000,000
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Bergeron, Raymond J; Wiegand, Jan; Singh, Shailendra (2009) Desferrithiocin analogue uranium decorporation agents. Int J Radiat Biol 85:348-61
Bergeron, Raymond J; Bharti, Neelam; Singh, Shailendra et al. (2009) Vibriobactin antibodies: a vaccine strategy. J Med Chem 52:3801-13