An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease

Habchi, Johnny; Arosio, Paolo; Perni, Michele; Costa, Ana Rita; Yagi-Utsumi, Maho; Joshi, Priyanka; Chia, Sean; Cohen, Samuel I.; Müller, M.; Linse, Sara; Nollen, Ellen A. A.; Dobson, Christopher M.; Knowles, Tuomas P. J.

doi:10.1126/sciadv.1501244

Cited by 196 publications

(269 citation statements)

References 55 publications

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“…In the light of this information, we decided to investigate whether compounds capable of altering the binding of α-synuclein to lipid membranes could be effective in inhibiting its aggregation. This study was stimulated by our recent finding that a small molecule, bexarotene, can suppress significantly the primary nucleation reaction that initiates the production of the Aβ 42 aggregates linked with Alzheimer's disease (AD) and reduces the associated toxicity in a Caenorhabditis elegans model of this disease (13).…”

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A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

Perni

Galvagnion

Maltsev

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The self-assembly of α-synuclein is closely associated with Parkinson’s disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic reduction of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson’s disease and related conditions.

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confidence: 99%

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

Perni

Galvagnion

Maltsev

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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262

369

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“…We introduce first a quasi-structure-based drug discovery (QSBDD) strategy, which builds on the recent finding that the small molecule bexarotene delays primary nucleation in Aβ42 aggregation (22) (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

“…We further evaluated the effects of the same small molecules in a C. elegans model of Aβ42-mediated dysfunction, denoted GMC101 (termed the Aβ-worm model) (22). In this model, Aβ42 is expressed in body wall muscle cells, where it forms aggregates and results in progressive paralysis (22).…”

Section: Rar and Rxr Ligands Inhibit Aβ42 Aggregation In Csf Solutionmentioning

confidence: 99%

“…In this model, Aβ42 is expressed in body wall muscle cells, where it forms aggregates and results in progressive paralysis (22). We assessed the effects of the small molecules on the fitness of the worms in terms of the frequency of body bends (i.e., motility) and the rate of their paralysis.…”

Section: Rar and Rxr Ligands Inhibit Aβ42 Aggregation In Csf Solutionmentioning

confidence: 99%

“…Indeed, it has been shown that inhibiting Aβ aggregation without a detailed understanding of the underlying microscopic processes could affect the toxicity in unexpected ways (21,22). For example, the inhibition of nucleation events may delay or decrease toxicity, whereas the inhibition of elongation may lead to an overall increase in toxicity (21,22). Therefore, effective therapeutic strategies must be aimed at targeting precise microscopic steps during the Aβ aggregation process (21,(23)(24)(25).…”

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Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease

Habchi

Chia

Limbocker

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The aggregation of the 42-residue form of the amyloid-β peptide (Aβ42) is a pivotal event in Alzheimer's disease (AD). The use of chemical kinetics has recently enabled highly accurate quantifications of the effects of small molecules on specific microscopic steps in Aβ42 aggregation. Here, we exploit this approach to develop a rational drug discovery strategy against Aβ42 aggregation that uses as a readout the changes in the nucleation and elongation rate constants caused by candidate small molecules. We thus identify a pool of compounds that target specific microscopic steps in Aβ42 aggregation. We then test further these small molecules in human cerebrospinal fluid and in a Caenorhabditis elegans model of AD. Our results show that this strategy represents a powerful approach to identify systematically small molecule lead compounds, thus offering an appealing opportunity to reduce the attrition problem in drug discovery.Alzheimer's disease | amyloid-β peptide | protein misfolding | drug discovery | protein aggregation A lzheimer's disease (AD) is, to date, an incurable neurodegenerative disorder that imposes substantial social and economic costs worldwide (1). According to the amyloid hypothesis, the aggregation of the amyloid-β peptide (Aβ) initiates a cascade of molecular events leading eventually to neuronal death (2-11). Because the presence of abnormal Aβ metabolism can be detected 10-20 years before the onset of AD (12, 13), early interventions may be possible before widespread and irreversible neurodegeneration has occurred. Although targeting Aβ accumulation has been pursued as a major potential therapeutic strategy against AD (14-17), no compound selected for this purpose has yet entered clinical use (18,19).Although these failures have raised doubts about the amyloid hypothesis (20), they can also be attributed to an incomplete knowledge of the molecular mechanisms by which the compounds tested so far affect the nucleation and growth of Aβ aggregates. Indeed, it has been shown that inhibiting Aβ aggregation without a detailed understanding of the underlying microscopic processes could affect the toxicity in unexpected ways (21,22). For example, the inhibition of nucleation events may delay or decrease toxicity, whereas the inhibition of elongation may lead to an overall increase in toxicity (21,22). Therefore, effective therapeutic strategies must be aimed at targeting precise microscopic steps during the Aβ aggregation process (21,(23)(24)(25).We describe here the development of a systematic pipeline based on chemical kinetics to identify a pool of candidate molecules directed against the aggregation of the 42-residue form of Aβ (Aβ42), and to understand the key chemical features responsible for their inhibitory activity. Results and DiscussionA Quasi-Structure-Based Drug Discovery Strategy. We introduce first a quasi-structure-based drug discovery (QSBDD) strategy, which builds on the recent finding that the small molecule bexarotene delays primary nucleation in Aβ42 aggregation (22) (Fig. 1A). Bec...

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A RaPID Macrocyclic Peptide That Inhibits the Formation of α‐Synuclein Amyloid Fibrils

Ikenoue

Oono

et al. 2023

ChemBioChem

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There is considerable interest in drug discovery targeting the aggregation of α‐synuclein (αSyn) since this molecular process is closely associated with Parkinson's disease. However, inhibiting αSyn aggregation remains a major challenge because of its highly dynamic nature which makes it difficult to form a stable binding complex with a drug molecule. Here, by exploiting Random non‐standard Peptides Integrated Discovery (RaPID) system, we identified a macrocyclic peptide, BD1, that could interact with immobilized αSyn and inhibit the formation of fibrils. Furthermore, improving the solubility of BD1 suppresses the co‐aggregation with αSyn fibrils while it kinetically inhibits more effectively without change in their morphology. We also revealed the molecular mechanism of kinetic inhibition, where peptides bind to fibril ends of αSyn, thereby preventing further growth of fibrils. These results suggest that our approach for generating non‐standard macrocyclic peptides is a promising approach for developing potential therapeutics against neurodegeneration.

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An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease

Abstract: An approved anticancer drug selectively targets the first step in the molecular cascade resulting in Alzheimer’s disease.

Cited by 196 publications

References 55 publications

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease

A RaPID Macrocyclic Peptide That Inhibits the Formation of α‐Synuclein Amyloid Fibrils

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