Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, Milan, Italy.
ChemMedChem. 2010 Jul 5;5(7):1015-25. doi: 10.1002/cmdc.201000082.
Beta(2)-microglobulin (beta(2)-m) is a protein responsible for a severe complication of long-term hemodialysis, known as dialysis-related amyloidosis, in which initial beta(2)-m misfolding leads to amyloid fibril deposition, mainly in the skeletal tissue. Whereas much attention is paid to understanding the complex mechanism of amyloid formation, the evaluation of small molecules that may bind beta(2)-m and possibly inhibit the aggregation process is still largely unexplored mainly because the protein lacks a specific active site. Based on our previous findings, we selected a pilot set of sulfonated molecules that are known to either bind or not to the protein, including binders that are anti-amyloidogenic. We show how a complementary approach, using high-resolution mass spectrometry and in silico studies, can offer rapid and precise information on affinity, as well as insight into the structural requisites that favour or disfavour the inhibitory activity. Overall, this approach can be used for predictive purposes and for a rapid screening of fibrillogenesis inhibitors.
β2-微球蛋白（β2-m）是一种蛋白质，它是长期血液透析患者发生一种严重并发症的罪魁祸首，这种并发症被称为透析相关性淀粉样变，其中β2-m 的初始错误折叠导致淀粉样纤维沉积，主要发生在骨骼组织中。虽然人们非常关注理解淀粉样形成的复杂机制，但评估可能与β2-m 结合并可能抑制聚集过程的小分子的工作在很大程度上仍未得到探索，主要是因为该蛋白缺乏特定的活性位点。基于我们之前的研究结果，我们选择了一组已知与该蛋白结合或不结合的磺化分子作为先导集，其中包括具有抗淀粉样变性的结合物。我们展示了如何使用高分辨率质谱和计算研究等互补方法，快速、精确地提供关于亲和力的信息，并深入了解有利于或不利于抑制活性的结构要求。总的来说，这种方法可用于预测目的和快速筛选纤维形成抑制剂。
