Inherited deficiency of galactose-1-phosphate uridyltransferase (GALT) can result in a potentially lethal disease called Classic Galactosemia. Although the neonatal lethality associated with this disease can be prevented through early diagnosis and a galactose-restricted diet, the lack of effective therapy continues to haunt the surviving children to their adulthood. 85% of treated galactosemic females suffer premature ovarian failure, while many others are inflicted with neurological disorders and developmental delay. Several lines of evidence suggested that elevated level of galactose-1-phosphate (gal-1-p), the product of galactokinase (GALK), is a major, if not sole, pathogenic mechanism in patients with galactosemia. We therefore hypothesize that elimination of gal-1-p production by inhibiting GALK will relieve GALT-deficient cells from galactose toxicity. To identify selective GALK inhibitors, we have purified large quantity of GALK and developed a robust high throughput (HTS) GALK assay, which will be used to screen over 300,000 chemical compounds of diverse structural scaffolds (Specific Aim 1). Positive hits identified in Aim 1 will be validated and characterized in Specific Aim 2 to assess their potency, selectivity and efficacy to reduce gal-1-p accumulation in galactose-intoxicated cells.

Public Health Relevance

Classic Galactosemia is a potentially lethal metabolic disorder that is included in the newborn screening programs of all 50 states in the U.S.. Although a galactose-restricted diet, which is the current standard of care, can prevent the neonatal lethality of this disorder, many well-treated patients continue to develop debilitating complications such as mental retardation, premature ovarian failure and other neurological deficits. The long-term goal of this project is to develop more effective therapies for this disorder. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
7R03MH085689-02
Application #
7884077
Study Section
Special Emphasis Panel (ZRG1-BST-J (52))
Program Officer
Yao, Yong
Project Start
2008-09-30
Project End
2011-01-31
Budget Start
2009-07-27
Budget End
2011-01-31
Support Year
2
Fiscal Year
2008
Total Cost
$16,113
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Odejinmi, Si; Rascon, Rg; Tang, M et al. (2011) Structure-activity analysis and cell-based optimization of human galactokinase inhibitors. ACS Med Chem Lett 2:667-672
Tang, M; Wierenga, K; Elsas, L J et al. (2010) Molecular and biochemical characterization of human galactokinase and its small molecule inhibitors. Chem Biol Interact 188:376-85
Lai, Kent; Elsas, Louis J; Wierenga, Klaas J (2009) Galactose toxicity in animals. IUBMB Life 61:1063-74