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Edited by William A. Eaton, National Institutes of Health, Bethesda, MD, and approved June 3, 2019 (received for review March 08, 2019)
Significance
A range of medical conditions, such as Alzheimer’s disease, Parkinson’s disease, and type II diabetes, are linked to protein aggregation. Thus, it is imperative to develop effective therapeutic strategies to combat protein aggregation. Here, we lay out a general approach for optimizing inhibition strategies based on small molecules that suppress nucleation or growth of aggregates. Our model reveals that the optimal timing of drug administration crucially depends on whether the compound inhibits primary nucleation, secondary nucleation, or the growth of aggregates. This approach could guide the rational design of therapeutic strategies to target protein aggregation diseases.
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-β(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.
Footnotes
↵1T.C.T.M. and C.A.W. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: lmahadev{at}g.harvard.edu.
Author contributions: L.M. conceived the research and approach; T.C.T.M. and C.A.W. performed research; T.C.T.M., C.A.W., and L.M. contributed new reagents/analytic tools; T.C.T.M., C.A.W., and L.M. analyzed data; and T.C.T.M., C.A.W., and L.M. wrote the paper.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1904090116/-/DCSupplemental.
Published under the PNAS license.
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Optimal control strategies for inhibition of protein aggregation
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- Biophysics and Computational Biology
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