Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias

Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread rare diseases have a deep impact in the life quality of the patients. Until recently, treatments were limited to palliative measures and kidney/liver transplants in the most severe forms. Efforts made to develop pharmacological treatments succeeded with the biotechnological agent lumasiran, a siRNA product against glycolate oxidase, which has become the first effective therapy to treat PH1. However, small molecule drugs have classically been preferred since they benefit from experience and have better pharmacological properties. The development of small molecule inhibitors designed against key enzymes of glyoxylate metabolism is on the focus of research. Enzyme inhibitors are successful and widely used in several diseases and their pharmacokinetic advantages are well known. In PHs, effective enzymatic targets have been determined and characterized for drug design and interesting inhibitory activities have been achieved both in vitro and in vivo. This review describes the most recent advances towards the development of small molecule enzyme inhibitors in the treatment of PHs, introducing the multi-target approach as a more effective and safe therapeutic option.

Hereditary disorders of oxalate metabolism: The primary hyperoxalurias

Primary hyperoxalurias (PHs) are rare inherited disorders characterized by an increased endogenous synthesis of oxalate caused by a deficiency in one of several liver and kidney enzymes involved in glyoxylate metabolism. The excess oxalate is eliminated from the body by the kidneys. High concentrations of oxalate in the urine increase the risk of calcium oxalate deposition in the kidney (resulting in nephrocalcinosis) and in the urinary tract (leading to urinary stones). Primary hyperoxaluria is characterized by recurring calcium oxalate stones, presenting from early childhood to late adult life. Over time, deposition of calcium oxalate crystals in kidney tissue leads to kidney damage with progressive loss of kidney function. Primary hyperoxaluria type 1 is the most severe form with a median age at end-stage renal failure reached during young adulthood. Patients with PH type 2 and PH type 3 may show preservation of kidney function well into adulthood. Systemic deposition of calcium oxalate (oxalosis) can follow kidney failure and increased plasma oxalate levels. Diagnosis is made by DNA analysis of peripheral blood samples, or more rarely by enzyme assay of liver biopsy tissue. Treatment relies on high fluid intake, inhibitors of calcium oxalate crystallization, and, when required, urological procedures for stone removal. Some patients with PH1 respond to vitamin B6 treatment. Management of end-stage renal failure is difficult as dialysis, whether haemo- or peritoneal, cannot match oxalate production. Isolated kidney transplantation places patients at risk of recurring oxalate deposition in the graft in PH1 patients not responsive to vitamin B6. Liver transplantation, usually combined with kidney transplantation, is a curative treatment for PH1 but carries significant risks.

Hereditary disorders of oxalate metabolism—the primary hyperoxalurias

Oxalate is an end-product of metabolism with no known useful biological function in humans. Anything that increases the body burden of oxalate, or elevates the concentration of oxalate in the urine, increases the risk of calcium oxalate deposition in the kidney and/or urinary tract, resulting in nephrocalcinosis and/or urinary stones....