Molecular Basis for Preventing α-Synuclein Aggregation by a Molecular Tweezer

Acharya, Srabasti; Safaie, Brian M.; Wongkongkathep, Piriya; Ivanova, Magdalena I.; Attar, Aida; Klärner, Frank Gerrit; Schräder, Thomas; Loo, Joseph A.; Bitan, Gal; Lapidus, Lisa J.

doi:10.1074/jbc.m113.524520

Cited by 87 publications

(126 citation statements)

References 33 publications

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“…Like other positively charged inhibitors, CLR01 interacts non-covalently with α-synuclein lysine residues. CLR01 interferes with fibrilpromoting hydrophobic and electrostatic interactions, likely, in part, by promoting the reconfiguration rate of the monomer [282]. CLR01 likely acts at nucleation and extension and inhibits at stoichiometric proportions, though disaggregation requires molar excess.…”

Section: Additional Inhibitory Interactions Between Smallmentioning

confidence: 98%

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Esposito

2014

Topics in Medicinal Chemistry

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α-Synuclein is a dynamic protein capable of assuming an ensemble of physiological and pathological structures. Its primary role in Parkinson's disease (PD) pathogenesis makes it an attractive though nonconventional therapeutic target. An understanding of α-synuclein intra-and intermolecular interactions and posttranslational modifications that lead to its misfolding, aggregation, accumulation, and cell-to-cell prion-like spreading is necessary to inform the design of α-synuclein-directed therapeutics. Native α-synuclein interacts with membranes and plays an important role in synaptic transmission and vesicle trafficking at the presynaptic terminal, though aggregated α-synuclein may be compromised in its ability to perform these functions. In addition to discussing α-synuclein structural biology, this chapter explores the variety of experimental therapeutic approaches currently under investigation that aim to maintain physiological α-synuclein levels, limit toxic aggregates, and lessen effects of misfolded α-synuclein on cellular homeostasis. For example, oligonucleotide-based approaches limit α-synuclein gene expression. In addition, select small molecules and peptides inhibit α-synuclein aggregation at substoichiometric concentrations in favor of less structured, more soluble, and less toxic oligomers that may be better substrates for clearance. Some small molecules also remodel existing α-synuclein fibrils. Modest chemical changes to these small molecules can greatly impact their mechanism of action. Finally, α-synuclein-directed immunotherapy enhances the lysosomal clearance of α-synuclein in experimental models and is currently in clinical trials. Other therapeutic approaches target α-synuclein posttranslational modifications, aim to limit its impact on mitochondria or its ability to alter gene expression in the nucleus.

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Section: Additional Inhibitory Interactions Between Smallmentioning

confidence: 98%

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Esposito

2014

Topics in Medicinal Chemistry

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“…In blood-brain-barrier studies, one hour following intravenous injection, brain levels of 3 H-CLR01, measured by scintillation counting, were ~2% of the levels found in the blood [71]. Importantly, the binding of CLR01 is highly labile and the affinity of the compound for Lys is in the micromolar range [68,69], although higher affinity may be achieved in certain cases, depending on the number of Lys residues in the target protein and the specific sequence of the protein [134]. The high lability and moderate affinity prevent …”

Section: Effects On Ttr Toxicity In Vivomentioning

confidence: 99%

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

Attar

Rahimi

Bitan

2013

Translational Neuroscience

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Abnormal protein folding and self-assembly causes over 30 cureless human diseases for which no diseasemodifying therapies are available. The common side to all these diseases is formation of aberrant toxic protein oligomers and amyloid fibrils. Both types of assemblies are drug targets, yet each presents major challenges to drug design, discovery, and development. In this review, we focus on two small molecules that inhibit formation of toxic amyloid protein assemblies -the green-tea derivative (-)-epigallocatechin-3-gallate (EGCG), which was identified through a combination of epidemiologic data and a compound library screen, and the molecular tweezer CLR01, whose inhibitory activity was discovered in our group based on rational reasoning, and subsequently confirmed experimentally. Both compounds act in a manner that is not specific to one particular protein and thus are useful against a multitude of amyloidogenic proteins, yet they act via distinct putative mechanisms. CLR01 disrupts protein aggregation through specific binding to lysine residues, whereas the mechanisms underlying the activity of EGCG are only recently beginning to unveil. We discuss current in vitro and, where available, in vivo literature related to EGCG and CLR01's effects on amyloid β-protein, α-synuclein, transthyretin, islet amyloid polypeptide, and calcitonin. We also describe the toxicity, pharmacokinetics, and mechanism of action of each compound.

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“…However, when k −1 ∼ k bi , then formation of O is rapid. The fast and medium diffusion coefficient regimes have been investigated previously in α-synuclein (26,43,44), but the prion protein exhibits dynamics in all three regimes. After formation of the oligomer, reconfiguration has less impact on subsequent aggregation steps.…”

Section: Discussionmentioning

confidence: 99%

“…However, aggregation is more likely when reconfiguration is about the same rate as bimolecular diffusion. We recently tested this model of aggregation by correlating intramolecular diffusion with aggregation propensity of α-synuclein under a variety solvent conditions, with mutation and with the use of small molecule inhibitors (26,(43)(44)(45).In the present study, we have investigated intramolecular diffusion of the Syrian hamster and rabbit prion proteins, two sequences with very different propensities to aggregate (46-50). Our results show that both prion sequences diffuse rapidly at high denaturants (6 M GdnHCl) and drops dramatically at low denaturant, accompanied by a slight collapse of the polypeptide chain.…”

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Prion protein dynamics before aggregation

Srivastava

Lapidus

2017

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

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Prion diseases, like Alzheimer's disease and Parkinson disease, are rapidly progressive neurodegenerative disorders caused by misfolding followed by aggregation and accumulation of protein deposits in neuronal cells. Here we measure intramolecular polypeptide backbone reconfiguration as a way to understand the molecular basis of prion aggregation. Our hypothesis is that when reconfiguration is either much faster or much slower than bimolecular diffusion, biomolecular association is not stable, but as the reconfiguration rate becomes similar to the rate of biomolecular diffusion, the association is more stable and subsequent aggregation is faster. Using the technique of Trp-Cys contact quenching, we investigate the effects of various conditions on reconfiguration dynamics of the Syrian hamster and rabbit prion proteins. This protein exhibits behavior in all three reconfiguration regimes. We conclude that the hamster prion is prone to aggregation at pH 4.4 because its reconfiguration rate is slow enough to expose hydrophobic residues on the same time scale that bimolecular association occurs, whereas the rabbit sequence avoids aggregation by reconfiguring 10 times faster than the hamster sequence.protein folding | protein aggregation | intramolecular diffusion | prion disease | astemizole P rion disease, also known as transmissible spongiform encephalopathy (TSE) is attributed to misfolding followed by ordered aggregation and accumulation of protein deposits in neuronal cells (1-3). According to the "protein-only" hypothesis, the central event in prion (PrP) pathogenesis is the conformational conversion of the cellular α-helical rich isoform, PrP C , into misfolded β-sheet rich isoform, PrP Sc (3-6). The infectious form PrP Sc is believed to catalyze the conversion of PrP C , thereby permitting transmission between individuals and species (3, 7-10). However, there is very little known about PrP C before ordered aggregation. No putative aggregation precursor structure has been definitively identified; the protein may even be completely unstructured. It is believed that PrP C repeatedly cycles between the cell surface (∼pH 7.0) and endocytic compartment that has a pH as low as 4. 4 (11, 12). Aggregated prion has been isolated from this compartment so it has been suggested that aggregation initiates in late endosomes (13,14). Also, the reduction of the disulfide bridge has been reported to augment misfolding in vitro and may play a significant role in prion pathogenesis (15)(16)(17)(18)(19)(20). However, the physical basis for aggregation of prion, particularly under certain solvent conditions, is still poorly understood.Protein folding is a diffusive search of the unfolded polypeptide chain over the energy landscape in conformational space for a minimum energy state (21). Intramolecular diffusion (diffusion of one part of the chain relative to another) plays a critical role by determining the rate at which an unfolded polypeptide chain finds its native state (22-25). It has been measured for various peptides and pro...

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Molecular Basis for Preventing α-Synuclein Aggregation by a Molecular Tweezer

Cited by 87 publications

References 33 publications

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

Prion protein dynamics before aggregation

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