DOI: 10.1101/456590Oct 30, 2018Paper

Optimal strategies for inhibition of protein aggregation

BioRxiv : the Preprint Server for Biology
Thomas C T MichaelsL Mahadevan

Abstract

Protein aggregation has been implicated in many diseases. 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. Here, we combine aggregation kinetics and control theory to determine optimal protocols which 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 Amyloid-beta aggregation of Alzheimer's disease in the model organism C. 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 new avenues for the design of rational therapies to control pathological protein aggregation.

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