M.W., J.C.M., C.J.D. development to treat PH1. Main hyperoxaluria type 1 (PH1, OMIM 259900) is definitely a rare autosomal recessive disorder caused by a functional deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT, EC 2.6.1.44) due to mutations in the gene. AGT catalyzes the transamination (detoxification) of glyoxylate to glycine in liver. In PH1 individuals, AGT deficiency results in build up of glyoxylate which is definitely then oxidized by lactate dehydrogenase (LDH) to form oxalate1,2. The calcium salt of oxalate is definitely highly insoluble and readily precipitates in cells, resulting in kidney stones, kidney damage/failure, and injury to additional organs. Clinically, PH1 is definitely characterized by an increase in synthesis and excretion of oxalate and progressive deposition of insoluble calcium oxalate in the kidney and urinary tract1. The abnormality eventually prospects to kidney failure and then calcium oxalate is deposited to almost all cells which accounts for all the pathological characteristics of PH1 including urolithiasis, nephrocalcinosis, and systemic oxalosis. Treatment options are limited for PH1. In some patients, the disease process can be slowed by pharmacological doses of vitamin B6 (pyridoxine), a precursor of pyridoxal phosphate. It can be halted only by liver transplantation which is a highly specialized form of enzyme alternative or gene therapy1. About 200 mutations in the gene encoding AGT have been found and the majority of them are point missense mutations3,4. These missense mutations lead to various types of protein dysfunction, including loss of catalytic activity, aggregation, accelerated proteolysis and, most amazingly, an unequalled protein trafficking defect in which AGT is definitely translocated to the mitochondria instead of the peroxisomes5,6. Mitochondrial AGT is definitely metabolically inefficient because the main site of synthesis of its substrate, glyoxylate, is the peroxisome. Many of the mutations, including the most common one, segregate on the background of Nrp2 the small polymorphic allele. The small allele varies from your more common major allele, most significantly by the presence of a base switch which encodes a Pro11Leu amino acid substitute. In Europeans and North Americans, FK-506 (Tacrolimus) potential treatment for PH1, other types of hyperoxaluria, and oxalate-mediated disorders7. However, previous search for GO inhibitors used the recombinant GO preparation or computational modeling that failed to identify active GO inhibitors at cellular level7,10,11. Searching for small molecule AGT activators and GO inhibitors that are active at cellular level is definitely a validated strategy for development of fresh therapeutics to treat PH1. We have applied a phenotypic screening approach to this task..