Madhusudhana Rasajna, Boyle Emily, Cen Yana
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA.
Center for Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, USA.
Biomedicines. 2025 Jun 13;13(6):1467. doi: 10.3390/biomedicines13061467.
Alzheimer's disease (AD) has become an increasingly pressing concern for the aging population. Current AD treatments mainly focus on cognitive and neuropsychiatric symptoms-with few FDA-approved treatments targeting disease progression itself. The amyloid cascade hypothesis describes the formation and accumulation of β-amyloid (Aβ) oligomers and plaques as a primary event in AD pathogenesis. This hypothesis has served as the foundation of disease-modifying treatment development over the last decade. Recently, glutaminyl cyclase (QC) has been identified as a potential drug target in the amyloid cascade. QC catalyzes the cyclization of Aβ to form pyroglutamated Aβ (pEAβ). pEAβ acts as the seed for the formation of Aβ plaques, thus preventing the formation of pEAβ via QC inhibition, and offers a promising therapeutic strategy against AD. Here, we offer an overview of the pathway QCI research has followed-from the initial testing of imidazole-based inhibitor scaffolds to QCI structural optimization via pharmacophore identification, Varoglutamstat entering clinical trials, and further avenues of bettering specificity and potency for future QCI development.
阿尔茨海默病（AD）已成为老龄化人口日益紧迫的关注问题。目前的AD治疗主要集中在认知和神经精神症状上，只有少数获得美国食品药品监督管理局（FDA）批准的治疗方法针对疾病进展本身。淀粉样蛋白级联假说将β-淀粉样蛋白（Aβ）寡聚体和斑块的形成与积累描述为AD发病机制中的主要事件。在过去十年中，这一假说一直是疾病修饰治疗开发的基础。最近，谷氨酰胺环化酶（QC）已被确定为淀粉样蛋白级联反应中的一个潜在药物靶点。QC催化Aβ环化形成焦谷氨酸化Aβ（pEAβ）。pEAβ作为Aβ斑块形成的种子，因此通过抑制QC来防止pEAβ的形成，并为AD提供了一种有前景的治疗策略。在这里，我们概述了QCI研究遵循的途径——从基于咪唑的抑制剂支架的初步测试到通过药效团识别进行QCI结构优化、瓦罗谷氨酯进入临床试验，以及未来QCI开发提高特异性和效力的进一步途径。
