Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Paulson School for Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138.
Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):10245-10250. doi: 10.1073/pnas.1807884115. Epub 2018 Sep 26.
To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure-activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aβ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.
为了开发针对蛋白质错误折叠疾病的有效治疗策略，一种有前途的方法是识别抑制蛋白质寡聚体形成的化合物。为了实现这一目标，我们报告了一种基于化学动力学的构效关系（SAR）方法，以定量估计小分子如何改变向寡聚体的反应通量。我们使用该估计值来推导出淀粉样β肽（Aβ）的化学规则，然后利用这些规则来优化起始化合物以减少 Aβ 寡聚体的形成。我们通过以系统的方式生成化学衍生物，将一种无活性的罗丹宁化合物转化为 Aβ 寡聚体形成的有效抑制剂，从而证明了这种方法的有效性。这些结果初步证明了直接针对蛋白质寡聚体产生的药物发现策略的潜力。
