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.

中文翻译：

---

谷氨酸脱氢酶作为高胰岛素血症高氨血症综合征治疗的有希望的靶点。

高胰岛素血症-高氨血症综合征（HHS）是一种以反复低血糖和血浆氨持续升高为特征的罕见疾病，可导致严重癫痫和永久性脑损伤。已经证明，谷氨酸脱氢酶 (GDH) 是线粒体基质中的一种酶，其功能突变是造成 HHS 的原因。因此，GDH已成为HHS小分子治疗干预的有希望的靶点。目前有几项药物化学研究针对 GDH，然而，迄今为止，没有报告的化合物进入临床试验。该观点总结了GDH抑制剂的发现和开发进展，包括HHS的发病机制、潜在结合位点、筛选方法和研究模型。