Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, via Aldo Moro, 2, 53100, Siena, SI, Italy.
Department of Biosciences, University of Milan, Milan, 20133, Italy.
J Biol Inorg Chem. 2018 Dec;23(8):1219-1226. doi: 10.1007/s00775-018-1605-1. Epub 2018 Aug 21.
Recent evidence links the role of human glutaminyl cyclase (hQC) to the amyloidogenic process involved in Alzheimer's disease (AD). hQC is a zinc enzyme present in neuronal tissue and its activity is responsible for the cyclization of N-terminal Gln or Glu β-amyloid peptides, leading to N-pyroglutamic acid peptides (pE-Aβ) that is probably a crucial event in the initiation and progress of the disease. Indeed, pE-containing peptides exhibit an elevated neurotoxicity and a tendency to aggregate. These observations render hQC inhibition an attractive strategy for developing new molecules active against AD. We present here the crystal structure of hQC in complex with SEN177, a newly designed molecule. The SEN177-binding mode to hQC differs from that of the known hQC inhibitors. SEN177 K on hQC is 20 nM, comparable or better than that of the most potent known hQC inhibitors PBD150 and PQ912. In addition, SEN177 already demonstrated relevant pharmacological properties in in vivo models of Huntington's disease. All these properties make SEN177 an important scaffold for developing molecules acting on AD and related diseases.
最近的证据将人类谷氨酰胺环化酶 (hQC) 的作用与阿尔茨海默病 (AD) 相关的淀粉样蛋白形成过程联系起来。hQC 是一种存在于神经元组织中的锌酶，其活性负责 N 端 Gln 或 Glu β-淀粉样肽的环化，导致 N-焦谷氨酸肽 (pE-Aβ)，这可能是疾病起始和进展的关键事件。事实上，含有 pE 的肽表现出更高的神经毒性和聚集倾向。这些观察结果使得 hQC 抑制成为开发针对 AD 的新分子的有吸引力的策略。我们在这里展示了 hQC 与 SEN177 复合物的晶体结构，SEN177 是一种新设计的分子。SEN177 与 hQC 的结合模式与已知的 hQC 抑制剂不同。SEN177 在 hQC 上的 K on 值为 20 nM，与最有效的已知 hQC 抑制剂 PBD150 和 PQ912 相当或更好。此外，SEN177 已经在亨廷顿病的体内模型中表现出相关的药理学特性。所有这些特性使 SEN177 成为开发针对 AD 和相关疾病的分子的重要支架。
