Optimal control strategies for inhibition of protein aggregation
Optimal control strategies for inhibition of protein aggregation
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DOI：
10.1073/pnas.1904090116
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发表时间：
2019-07-16
影响因子：
11.1
通讯作者：
Mahadevan, L.
中科院分区：
文献类型：
--
作者：
Michaels, Thomas C. T.;Weber, Christoph A.;Mahadevan, L.
蛋白质聚集与许多医学疾病有关，包括阿尔茨海默病和帕金森病。这些疾病的潜在治疗策略提出使用药物来抑制聚集过程中的特定分子事件。然而，可行的治疗方案需要平衡药物的功效与毒性，同时考虑分子水平上的聚集和抑制的潜在事件。为了解决这个关键问题，我们联合收割机在这里蛋白质聚集动力学和控制理论，以确定最佳的协议，防止蛋白质聚集通过特定的反应途径。我们发现，初级和原纤维依赖的次级成核的最佳抑制需要根本不同的给药方案。我们测试我们的方法的有效性的实验数据的淀粉样蛋白β（1-42）肽的阿尔茨海默病的模式生物秀丽隐杆线虫的聚集。我们的研究结果提出并回答了蛋白质聚集的分子基础和抑制蛋白质聚集的最佳策略之间的联系问题，为设计合理的治疗方法来控制病理性蛋白质聚集开辟了途径。
Protein aggregation has been implicated in many medical disorders, including Alzheimer's and Parkinson's diseases. Potential therapeutic strategies for these diseases propose the use of drugs to inhibit specific molecular events during the aggregation process. However, viable treatment protocols require balancing the efficacy of the drug with its toxicity, while accounting for the underlying events of aggregation and inhibition at the molecular level. To address this key problem, we combine here protein aggregation kinetics and control theory to determine optimal protocols that prevent protein aggregation via specific reaction pathways. We find that the optimal inhibition of primary and fibril-dependent secondary nucleation require fundamentally different drug administration protocols. We test the efficacy of our approach on experimental data for the aggregation of the amyloid-beta (1-42) peptide of Alzheimer's disease in the model organism Caenorhabditis elegans. Our results pose and answer the question of the link between the molecular basis of protein aggregation and optimal strategies for inhibiting it, opening up avenues for the design of rational therapies to control pathological protein aggregation.