Optimal strategies for inhibition of protein aggregation
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Abstract
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-(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.