Escaping amyloid fate

Roberts, Blake E; Shorter, James

doi:10.1038/nsmb0608-544

Cited by 36 publications

(41 citation statements)

References 26 publications

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“…40 Effective inhibition or modulation of the aberrant assembly process therefore is an appealing strategy for preventing and/or treating these diseases. Achieving this goal, however, is complicated due to the metastable nature of amyloidogenic protein oligomers and the unfavorable characteristics of amyloid fibrils as targets 41,42 . Though amyloidogenic proteins comprise distinct amino acid sequences, amyloid fibrils 2 and oligomers of amyloidogenic proteins 38 each share a great deal of structural similarity, which largely is sequence-independent.…”

Section: Discussionmentioning

confidence: 99%

Lysine-Specific Molecular Tweezers Are Broad-Spectrum Inhibitors of Assembly and Toxicity of Amyloid Proteins

Sinha

Lopes²,

et al. 2011

J. Am. Chem. Soc.

269

455

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Amyloidoses are diseases characterized by abnormal protein folding and self-assembly, for which no cure is available. Inhibition or modulation of abnormal protein self-assembly therefore is an attractive strategy for prevention and treatment of amyloidoses. We examined Lys-specific molecular tweezers and discovered a lead compound termed CLR01, which is capable of inhibiting the aggregation and toxicity of multiple amyloidogenic proteins by binding to Lys residues and disrupting hydrophobic and electrostatic interactions important for nucleation, oligomerization, and fibril elongation. Importantly, CLR01 shows no toxicity at concentrations substantially higher than those needed for inhibition. We used amyloid β-protein (Aβ) to further explore the binding site(s) of CLR01 and the impact of its binding on the assembly process. Mass-spectrometry and solution-state NMR demonstrated binding of CLR01 to the Lys residues in Aβ at the earliest stages of assembly. The resulting complexes were indistinguishable in size and morphology from Aβ oligomers but were non-toxic and were not recognized by the oligomer-specific antibody A11. Thus, CLR01 binds already at the monomer stage and modulates the assembly reaction into formation of non-toxic structures. The data suggest that molecular tweezers are unique, process-specific inhibitors of aberrant protein aggregation and toxicity, which hold promise for developing disease-modifying therapy for amyloidoses.

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Section: Discussionmentioning

confidence: 99%

Lysine-Specific Molecular Tweezers Are Broad-Spectrum Inhibitors of Assembly and Toxicity of Amyloid Proteins

Sinha

Lopes²,

et al. 2011

J. Am. Chem. Soc.

269

455

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“…The topologies of a variety of amyloid fibrils have been determined 2,3 and these have provide some mechanistic insights. However, the currently held view is that β-sheet oligomers are the toxic species 4,5 of these diseases rather than the mature fibrils. Hence, developing therapeutic strategies that can target the earliest stages of amyloidogenesis has become a prominent feature of protein folding disease research.…”

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confidence: 99%

Binding interactions of agents that alter α-synuclein aggregation

et al. 2015

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Further examination of peptides with well-folded antiparallel β strands as inhibitors of amyloid formation from α-synuclein has resulted in more potent inhibitors. Several of these had multiple Tyr residues and represent a new lead for inhibitor design by small peptides that do not divert α-synuclein to non-amyloid aggregate formation. The most potent inhibitor obtained in this study is a backbone cyclized version of a previously studied β hairpin, designated as WW2, with a cross-strand Trp/Trp cluster. The cyclization was accomplished by adding a d-Pro-l-Pro turn locus across strand termini. At a 2:1 peptide to α-synuclein ratio, cyclo-WW2 displays complete inhibition of β-structure formation. Trp-bearing antiparallel β-sheets held together by a disulphide bond are also potent inhibitors. 15N HSQC spectra of α-synuclein provided new mechanistic details. The time course of 15N HSQC spectral changes observed during β-oligomer formation has revealed which segments of the structure become part of the rigid core of an oligomer at early stages of amyloidogenesis and that the C-terminus remains fully flexible throughout the process. All of the effective peptide inhibitors display binding-associated titration shifts in 15N HSQC spectra of α-synuclein in the C-terminal Q109-E137 segment. Cyclo-WW2, the most potent inhibitor, also displays titration shifts in the G41-T54 span of α-synuclein, an additional binding site. The earliest aggregation event appears to be centered about H50 which is also a binding site for our most potent inhibitor.

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“…A general conclusion of these studies is that many small molecules redirect the aggregation cascade rather than inhibiting it completely (26). In hindsight, this finding is logical based on the large amount of buried surface area within protein aggregates compared with the small size of inhibitor molecules (27,28). Therefore, using small molecules to alter the nucleation pathway by disrupting specific intermolecular contacts or promoting atypical ones appears to be a more feasible approach to preventing formation of toxic aggregates than antagonizing all possible intermolecular contacts.…”

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confidence: 99%

Aromatic Small Molecules Remodel Toxic Soluble Oligomers of Amyloid β through Three Independent Pathways

Ladiwala

Dordick

Tessier

2011

Journal of Biological Chemistry

177

173

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In protein conformational disorders ranging from Alzheimer to Parkinson disease, proteins of unrelated sequence misfold into a similar array of aggregated conformers ranging from small oligomers to large amyloid fibrils. Substantial evidence suggests that small, prefibrillar oligomers are the most toxic species, yet to what extent they can be selectively targeted and remodeled into non-toxic conformers using small molecules is poorly understood. We have evaluated the conformational specificity and remodeling pathways of a diverse panel of aromatic small molecules against mature soluble oligomers of the A␤42 peptide associated with Alzheimer disease. We find that small molecule antagonists can be grouped into three classes, which we herein define as Class I, II, and III molecules, based on the distinct pathways they utilize to remodel soluble oligomers into multiple conformers with reduced toxicity. Class I molecules remodel soluble oligomers into large, off-pathway aggregates that are non-toxic. Moreover, Class IA molecules also remodel amyloid fibrils into the same off-pathway structures, whereas Class IB molecules fail to remodel fibrils but accelerate aggregation of freshly disaggregated A␤. In contrast, a Class II molecule converts soluble A␤ oligomers into fibrils, but is inactive against disaggregated and fibrillar A␤. Class III molecules disassemble soluble oligomers (as well as fibrils) into low molecular weight species that are non-toxic. Strikingly, A␤ non-toxic oligomers (which are morphologically indistinguishable from toxic soluble oligomers) are significantly more resistant to being remodeled than A␤ soluble oligomers or amyloid fibrils. Our findings reveal that relatively subtle differences in small molecule structure encipher surprisingly large differences in the pathways they employ to remodel A␤ soluble oligomers and related aggregated conformers.A central tenet of protein folding is that a given amino acid sequence encodes a single folded structure (1). By analogy, one would expect that a given protein sequence would encode a single misfolded structure (e.g. a single amyloid fibril conformation). Instead, each protein sequence encodes numerous aggregated isoforms that possess unique secondary and tertiary structures (2-12). Previous work has firmly established that small, prefibrillar conformers (herein referred to as soluble oligomers) of diverse polypeptides are the most toxic aggregates both in vitro and in vivo (11,(13)(14)(15)(16)(17). However, elucidating the structural attributes of such toxic conformers that differentiate them from their non-toxic counterparts has proven difficult (see Refs. 11 and 18 -22 for recent progress).Significant evidence linking protein misfolding to cellular toxicity in numerous aggregation disorders has motivated the search for small molecules that prevent aggregation (see Refs. 23-25, and references therein). A general conclusion of these studies is that many small molecules redirect the aggregation cascade rather than inhibiting it completely (26). In hind...

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Escaping amyloid fate

Cited by 36 publications

References 26 publications

Lysine-Specific Molecular Tweezers Are Broad-Spectrum Inhibitors of Assembly and Toxicity of Amyloid Proteins

Lysine-Specific Molecular Tweezers Are Broad-Spectrum Inhibitors of Assembly and Toxicity of Amyloid Proteins

Binding interactions of agents that alter α-synuclein aggregation

Aromatic Small Molecules Remodel Toxic Soluble Oligomers of Amyloid β through Three Independent Pathways

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