Glutamate Dehydrogenase as a Promising Target for Hyperinsulinism
Hyperammonemia Syndrome Therapy

Yunfei       Bian; Wei       Hou; Xinrou       Chen; Jinzhang       Fang; Ning       Xu; Benfang    Helen    Ruan
Abstract

Hyperinsulinism-hyperammonemia syndrome (HHS) is a rare disease characterized by recurrent hypoglycemia and persistent elevation of plasma ammonia, and it can lead to severe epilepsy and permanent brain damage. It has been demonstrated that functional mutations of glutamate dehydrogenase (GDH), an enzyme in the mitochondrial matrix, are responsible for the HHS. Thus, GDH has become a promising target for the small molecule therapeutic intervention of HHS. Several medicinal chemistry studies are currently aimed at GDH, however, to date, none of the compounds reported has been entered clinical trials. This perspective summarizes the progress in the discovery and development of GDH inhibitors, including the pathogenesis of HHS, potential binding sites, screening methods, and research models. Future therapeutic perspectives are offered to provide a reference for discovering potent GDH modulators and encourage additional research that will provide more comprehensive guidance for drug development.
Keywords: Hyperinsulinism hyperammonemia syndrome (HHS), glutamate dehydrogenase (GDH), screening method, enzyme inhibitors, drug discovery, in vitro/in vivo models.
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Cite As
Current Medicinal Chemistry

Glutamate Dehydrogenase as a Promising Target for Hyperinsulinism Hyperammonemia Syndrome Therapy

Abstract
