Bolognesi Maria Laura, Bongarzone Salvatore, Aulic Suzana, Ai Tran Hoang Ngoc, Prati Federica, Carloni Paolo, Legname Giuseppe
Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Division of Imaging Sciences & Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, UK.
Future Med Chem. 2015;7(16):2113-20. doi: 10.4155/fmc.15.79. Epub 2015 Oct 29.
The main pathogenic event of prion disorders has been identified in the deposition of the disease-associated prion protein (PrP(Sc)), which is accompanied by metal dyshomeostasis.
The multitarget-directed ligand 1, designed by combining a heteroaromatic prion recognition motif to an 8-hydroxyquinoline metal chelator, has been developed as a potential antiprion disease-modifying agent. Importantly, 1 was found to effectively clear PrP(Sc) from scrapie-infected cells, and, at the same time, inhibit metal-induced prion aggregation and reactive oxygen species generation. 1 was also characterized in terms of pharmacokinetic properties in a preliminary in vitro investigation.
Compound 1 has emerged as a suitable lead candidate against prion diseases and as a good starting point for a further optimization process.
朊病毒疾病的主要致病事件已被确定为与疾病相关的朊病毒蛋白（PrP(Sc)）的沉积，这伴随着金属稳态失衡。
通过将杂芳族朊病毒识别基序与8-羟基喹啉金属螯合剂相结合设计的多靶点导向配体1已被开发为一种潜在的抗朊病毒疾病修饰剂。重要的是，发现1能有效清除来自瘙痒病感染细胞的PrP(Sc)，同时抑制金属诱导的朊病毒聚集和活性氧的产生。在初步的体外研究中，还对1的药代动力学性质进行了表征。
化合物1已成为抗朊病毒疾病的合适先导候选物，也是进一步优化过程的良好起点。
