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Executive Summary:

Primary hyperoxaluria (PH-1) is a human genetic disease due to a deficiency of alanine-glyoxylate aminotransferase (AGT) activity in hepatocytes. This enzyme detoxifies glyoxylate by transamination to glycine. A lack of AGT activity means the activation of alternative metabolic routes that lead to an excessive oxalate formation. This saturates the renal excretion capacity and accumulates as insoluble crystals. This accumulation of oxalate first damages the kidneys and the disease enters a critical phase when the patient reaches end-stage renal disease because hemodialysis cannot prevent the wide spread accumulation of oxalate (oxalosis), which is life-threatening. Renal and hepatic transplants become necessary to preserve the life of these patients.

Glycolate is one important source of glyoxylate in humans. The enzyme in charge of the oxidation of glycolate into glyoxylate is called glycolate-oxidase (GO). Thus, it would be beneficial for PH-1 patients to reduce the production of glyoxylate by inhibiting the GO activity, a strategy known as 'substrate reduction therapy' (SRT). Recent studies using genetically modified mice have identified GO as an efficient and harmless target for SRT in PH-1. In addition, the structure of human and mouse GO has been recently elucidated, which facilitates the rational design of small molecules capable of inhibiting GO. Based on these findings, we propose to explore the pharmacological inhibition of GO. Those molecules with capacity to inhibit GO would potentially lead to drugs useful in the treatment of PH-1 and potentially also other diseases involving oxalate accumulation.

A number of final molecules potentially active as enzyme GO inhibitors has been prepared. Main biological testing on GO inhibition is still going on. Biological screening of the final probes in search for other activities has shown important neuroprotective activities for some of the hits. To our delight, those compounds presenting neuroprotective activities resulted in addition no cytotoxic. This has opened new research possibilities to us and further investigations are being carried in search for more potent hits. Biological testing for GO inhibitory activity is made by our collaborator, Prof. Eduardo Salido (University of La Laguna). Neuroprotective and cytotoxicity assays, are made through our collaboration with Dr. Nuria de Pedro in Medina Foundation (

This project deals with the preparation of small molecules with enzyme GO inhibitory activity which are expected to find application in the treatment of PH-1. This way, the project addresses a relevant scientific and social problem, related to the study and knowledge of “orphan diseases”. This is a field of therapeutics which lacks the attention of the pharmaceutical industry. Therefore our efforts are directed to a minority of the population which feels to be forsaken. The existence of programs which focus on improving the life quality of those suffering orphan diseases are an important support for these patients.