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.
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. ? ? ?
| Liu, Li; Tang, Manshu; Walsh, Martin J et al. (2015) Structure activity relationships of human galactokinase inhibitors. Bioorg Med Chem Lett 25:721-7 |
| Tang, M; Odejinmi, S I; Allette, Y M et al. (2011) Identification of novel small molecule inhibitors of 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP-ME) kinase of Gram-negative bacteria. Bioorg Med Chem 19:5886-95 |
| 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 |
