Title:Glutamate Dehydrogenase as a Promising Target for Hyperinsulinism
Hyperammonemia Syndrome Therapy
Volume: 29
Issue: 15
Author(s): Yunfei Bian, Wei Hou, Xinrou Chen, Jinzhang Fang, Ning Xu*Benfang Helen Ruan
Affiliation:
- College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology, Zhejiang University
of Technology, Hantgzhou 310014, P.R. China
Keywords:
Hyperinsulinism hyperammonemia syndrome (HHS), glutamate dehydrogenase (GDH), screening method, enzyme inhibitors, drug discovery, in vitro/in vivo models.
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.