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3. Small-molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer's disease

Author

Benedetta Mannini, Roberta Pierattelli, Thomas Löhr, Massimiliano Bonomi, Carlo Camilloni, Thomas C. T. Michaels, Francesco Simone Ruggeri, Gabriella T. Heller, Alfonso De Simone, Michele Vendruscolo, Francesco A. Aprile, Christopher M. Dobson, Ryan Limbocker, Michele Perni, Isabella C. Felli, Tuomas P. J. Knowles, Heller, Gabriella T [0000-0002-5672-0467], Aprile, Francesco A [0000-0002-5040-4420], Perni, Michele [0000-0001-7593-8376], Ruggeri, Francesco Simone [0000-0002-1232-1907], Mannini, Benedetta [0000-0001-6812-7348], Löhr, Thomas [0000-0003-2969-810X], Bonomi, Massimiliano [0000-0002-7321-0004], Camilloni, Carlo [0000-0002-9923-8590], De Simone, Alfonso [0000-0001-8789-9546], Felli, Isabella C [0000-0002-6018-9090], Pierattelli, Roberta [0000-0001-7755-0885], Knowles, Tuomas PJ [0000-0002-7879-0140], Dobson, Christopher M [0000-0002-5445-680X], Vendruscolo, Michele [0000-0002-3616-1610], Apollo - University of Cambridge Repository, Heller, G. T., Aprile, F. A., Michaels, T. C. T., Limbocker, R., Perni, M., Ruggeri, F. S., Mannini, B., Lohr, T., Bonomi, M., Camilloni, C., de Simone, A., Felli, I. C., Pierattelli, R., Knowles, T. P. J., Dobson, C. M., Vendruscolo, M., University of Cambridge [UK] (CAM), Imperial College London, Harvard University, Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano = University of Milan (UNIMI), University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli Studi di Firenze = University of Florence (UniFI), Funding: G.T.H. is supported by the Gates Cambridge Trust and the Rosalind Franklin Research Fellowship at Newnham College, Cambridge, F.A.A. is supported by UK Research and Innovation (Future Leaders Fellowship MR/S033947/1) and the Alzheimer’s Society, UK (317, 511), R.L. is supported by the Gates Cambridge Trust, TCTM by Peterhouse, Cambridge and the Swiss National Science Foundation, and F.S.R. is supported by Darwin College and the Swiss National Foundation (grant numbers P300P2_171219 and P2ELP2_162116, respectively). We acknowledge ARCHER UK National Supercomputing Service under ARCHER Leadership project (grant number e510) and PRACE for awarding us access to MareNostrum at Barcelona Supercomputing Center (BSC), Spain for metadynamic metainference simulations. Parameterization of 10074-G5 was performed using resources provided by the Cambridge Service for Data Driven Discovery (CSD3) operated by the University of Cambridge Research Computing Service (www.csd3.cam.ac.uk), provided by Dell EMC and Intel using Tier-2 funding from the Engineering and Physical Sciences Research Council (capital grant EP/P020259/1), and DiRAC funding from the Science and Technology Facilities Council (www.dirac.ac.uk). MALDI mass spectrometry measurements were performed by L. Packman at the Protein and Nucleic Acid Chemistry Facility (PNAC) at the Department of Biochemistry, University of Cambridge. The NMR measurements were supported by the iNEXT H2020 Programme (EC contract no. 653706). OW450 C. elegans were donated by E. Nollen. BLI measurements were performed in the Biophysics facility at the Department of Biochemistry, University of Cambridge. The work was also supported by the Centre for Misfolding Diseases and the INCEPTION project ANR-16-CONV-0005., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Harvard University [Cambridge], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano [Milano] (UNIMI), University of Naples Federico II, and Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)

Subjects
Amyloid beta, In silico, Biophysics, Intrinsically disordered proteins, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Drug Discovery, medicine, Humans, Life Science, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, Research Articles, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Amyloid beta-Peptides, biology, Drug discovery, Chemistry, SciAdv r-articles, Conformational entropy, Small molecule, Peptide Fragments, 3. Good health, Mechanism of action, biology.protein, Small molecule binding, medicine.symptom, Hydrophobic and Hydrophilic Interactions, 030217 neurology & neurosurgery, Research Article
Abstract

A small molecule binds to a disordered protein in its monomeric form, preventing its aggregation linked to Alzheimer’s disease., Disordered proteins are challenging therapeutic targets, and no drug is currently in clinical use that modifies the properties of their monomeric states. Here, we identify a small molecule (10074-G5) capable of binding and sequestering the intrinsically disordered amyloid-β (Aβ) peptide in its monomeric, soluble state. Our analysis reveals that this compound interacts with Aβ and inhibits both the primary and secondary nucleation pathways in its aggregation process. We characterize this interaction using biophysical experiments and integrative structural ensemble determination methods. We observe that this molecule increases the conformational entropy of monomeric Aβ while decreasing its hydrophobic surface area. We also show that it rescues a Caenorhabditis elegans model of Aβ-associated toxicity, consistent with the mechanism of action identified from the in silico and in vitro studies. These results illustrate the strategy of stabilizing the monomeric states of disordered proteins with small molecules to alter their behavior for therapeutic purposes.

Published
2020

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