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

Miguel Xavier Fernandes,Joaquin Altarejos,Maria Dolores Moya-Garzon,Sofia Salido,Juan Roberto Rodriguez-Madoz,Jose Antonio Gomez-Vidal,Eduardo Salido,Alfonso Alejo-Armijo,Monica Diaz-Gavilan

doi:10.3390/jpm11020074

Abstract

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.

Highlights

Glycolate oxidase (GO; EC 1.1.3.15) is a FMN-dependent flavoenzyme that belongs to the α-hydroxy acid oxidase family [79,80], which includes Pseudomonas putida mandelate dehydrogenase (MDH), the flavin-binding domain of yeast flavocytochrome b2 (FCB2), rat long chain hydroxy acid oxidase (LCHAO), and spinach glycolate oxidase [81]
It has been published that small interfering RNAs (siRNAs) of lactate dehydrogenase A (LDHA) reduces the production of calcium oxalate in hepatic cells by reducing the production of LDHA into the liver [55,56]
One of the concerns of using a biological drug, siRNA, in a life-long repeated administration is the lack of clinical experience with this kind of treatments when compared with the use of classical small-molecule drugs for other diseases

Summary

Primary Hyperoxalurias

Primary hyperoxaluria (PH) is a rare disease of liver metabolism that results in excess oxalate production and urine excretion (hyperoxaluria). Thispopulation severe disease caused byofgenetic changes that alter uals could be a good estimate [2] This severe disease is caused by genetic changes glyoxylate and hydroxyproline metabolism resulting in overproduction of oxalatethat by the alter [3]. Glyoxylate and hydroxyproline metabolism resulting overproduction of oxalate liver. All three forms of PH are inherited as gene (coding 4-hydroxy-2-oxoglutarate aldolase 1, HOGA1). Loss of function mutations in any of these three genes result in a deficit to detoxify Loss of function mutations in any of these three genes result in a deficit to detoxify glyoxylate, which is converted into oxalate by hepatic lactate dehydrogenase (LDH). Patientswith withprimary primary hyperoxaluria crystals and hyperoxaluexperience high concentrations of oxalate in the urine from birth.

Schematic

Glycolate Oxidase Inhibitors

Lactate Dehydrogenase Inhibitors

Enzymatic Assays

Cellular Models

Human Cellular Models

Findings

Conclusions and Outlook