PDF(Pubmed)
Abstract：
An imbalance between production and excretion of amyloid β peptide (Aβ) in the brain tissues of Alzheimer\'s disease (AD) patients leads to Aβ accumulation and the formation of noxious Aβ oligomers/plaques. A promising approach to AD prevention is the reduction of free Aβ levels by directed enhancement of Aβ binding to its natural depot, human serum albumin (HSA). We previously demonstrated the ability of specific low-molecular-weight ligands (LMWLs) in HSA to improve its affinity for Aβ. Here we develop this approach through a bioinformatic search for the clinically approved AD-related LMWLs in HSA, followed by classification of the candidates according to the predicted location of their binding sites on the HSA surface, ranking of the candidates, and selective experimental validation of their impact on HSA affinity for Aβ. The top 100 candidate LMWLs were classified into five clusters. The specific representatives of the different clusters exhibit dramatically different behavior, with 3- to 13-fold changes in equilibrium dissociation constants for the HSA-Aβ40 interaction: prednisone favors HSA-Aβ interaction, mefenamic acid shows the opposite effect, and levothyroxine exhibits bidirectional effects. Overall, the LMWLs in HSA chosen here provide a basis for drug repurposing for AD prevention, and for the search of medications promoting AD progression.
摘要：
阿尔茨海默病（AD）患者脑组织中淀粉样β肽（Aβ）的产生和排泄之间的不平衡导致Aβ积累和有害的Aβ寡聚体/斑块的形成。预防AD的一种有希望的方法是通过定向增强Aβ与其天然储库的结合来降低游离Aβ水平。人血清白蛋白（HSA）。我们先前证明了HSA中特定低分子量配体（LMWL）改善其对Aβ的亲和力的能力。在这里，我们通过生物信息学搜索HSA中临床批准的AD相关LMWL来开发这种方法，然后根据其结合位点在HSA表面上的预测位置对候选物进行分类，候选人的排名，并选择性实验验证了它们对HSA对Aβ亲和力的影响。前100个候选LMWL被分为五个簇。不同集群的特定代表表现出截然不同的行为，HSA-Aβ40相互作用的平衡解离常数变化为3至13倍：泼尼松有利于HSA-Aβ相互作用，甲芬那酸显示相反的效果，和左甲状腺素表现出双向作用。总的来说,这里选择的HSA中的LMWL为AD预防的药物再利用提供了基础，并寻找促进AD进展的药物。
