scholarly journals Proteasome Activation to Combat Proteotoxicity

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2841 ◽  
Author(s):  
Corey L. Jones ◽  
Jetze J. Tepe
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Small Molecule ◽  
Therapeutic Intervention ◽  
Intrinsically Disordered Proteins ◽  
Structural Data ◽  
Disordered Proteins ◽  
Native Protein ◽  
Intrinsically Disordered ◽  
Aged Cell ◽  
Lateral Sclerosis

Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer’s Diseases (AD). Many strategies for therapeutic intervention in proteotoxic pathologies have been put forth; one of the most promising is bolstering the efficacy of the proteasome to restore normal proteostasis. This strategy is ideal as monomeric precursors and oxidatively damaged proteins, so called “intrinsically disordered proteins” (IDPs), are targeted by the proteasome. This review will provide an overview of disorders in proteins, both intrinsic and acquired, with a focus on susceptibility to proteasomal degradation. We will then examine the proteasome with emphasis on newly published structural data and summarize current known small molecule proteasome activators.

scholarly journals Small Molecule Binding of Intrinsically Disordered Proteins: Multiple Binders on Multiple Sites

2009 ◽  
Vol 96 (3) ◽  
pp. 319a
Author(s):  
Dalia Hammoudeh ◽  
Ariele Viachava-Follis ◽  
Edward V. Prochownik ◽  
Steven J. Metallo
Keyword(s):  
Small Molecule ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered

A Fragment-Based Method of Creating Small-Molecule Libraries to Target the Aggregation of Intrinsically Disordered Proteins

2016 ◽  
Vol 18 (3) ◽  
pp. 144-153 ◽  
Author(s):  
Priyanka Joshi ◽  
Sean Chia ◽  
Johnny Habchi ◽  
Tuomas P. J. Knowles ◽  
Christopher M. Dobson ◽  
...  
Keyword(s):  
Small Molecule ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Small Molecule Libraries

scholarly journals Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA

2020 ◽  
Vol 117 (3) ◽  
pp. 1457-1467 ◽  
Author(s):  
Peiyuan Zhang ◽  
Hye-Jin Park ◽  
Jie Zhang ◽  
Eunsung Junn ◽  
Ryan J. Andrews ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Intrinsically Disordered Proteins ◽  
Lewy Bodies ◽  
Disordered Proteins ◽  
Lewy Neurites ◽  
Protein Levels ◽  
Intrinsically Disordered ◽  
In Cells

Many proteins are refractory to targeting because they lack small-molecule binding pockets. An alternative to drugging these proteins directly is to target the messenger (m)RNA that encodes them, thereby reducing protein levels. We describe such an approach for the difficult-to-target protein α-synuclein encoded by the SNCA gene. Multiplication of the SNCA gene locus causes dominantly inherited Parkinson’s disease (PD), and α-synuclein protein aggregates in Lewy bodies and Lewy neurites in sporadic PD. Thus, reducing the expression of α-synuclein protein is expected to have therapeutic value. Fortuitously, the SNCA mRNA has a structured iron-responsive element (IRE) in its 5′ untranslated region (5′ UTR) that controls its translation. Using sequence-based design, we discovered small molecules that target the IRE structure and inhibit SNCA translation in cells, the most potent of which is named Synucleozid. Both in vitro and cellular profiling studies showed Synucleozid directly targets the α-synuclein mRNA 5′ UTR at the designed site. Mechanistic studies revealed that Synucleozid reduces α-synuclein protein levels by decreasing the amount of SNCA mRNA loaded into polysomes, mechanistically providing a cytoprotective effect in cells. Proteome- and transcriptome-wide studies showed that the compound’s selectivity makes Synucleozid suitable for further development. Importantly, transcriptome-wide analysis of mRNAs that encode intrinsically disordered proteins revealed that each has structured regions that could be targeted with small molecules. These findings demonstrate the potential for targeting undruggable proteins at the level of their coding mRNAs. This approach, as applied to SNCA, is a promising disease-modifying therapeutic strategy for PD and other α-synucleinopathies.

scholarly journals Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 146 ◽  
Author(s):  
Supriyo Bhattacharya ◽  
Xingcheng Lin
Keyword(s):  
Single Molecule ◽  
Degrees Of Freedom ◽  
Intrinsically Disordered Proteins ◽  
Structural Information ◽  
Conformational Dynamics ◽  
Resonance Energy ◽  
Structural Data ◽  
Disordered Proteins ◽  
Conformational Ensemble ◽  
Intrinsically Disordered

Intrinsically disordered proteins (IDP) are abundant in the human genome and have recently emerged as major therapeutic targets for various diseases. Unlike traditional proteins that adopt a definitive structure, IDPs in free solution are disordered and exist as an ensemble of conformations. This enables the IDPs to signal through multiple signaling pathways and serve as scaffolds for multi-protein complexes. The challenge in studying IDPs experimentally stems from their disordered nature. Nuclear magnetic resonance (NMR), circular dichroism, small angle X-ray scattering, and single molecule Förster resonance energy transfer (FRET) can give the local structural information and overall dimension of IDPs, but seldom provide a unified picture of the whole protein. To understand the conformational dynamics of IDPs and how their structural ensembles recognize multiple binding partners and small molecule inhibitors, knowledge-based and physics-based sampling techniques are utilized in-silico, guided by experimental structural data. However, efficient sampling of the IDP conformational ensemble requires traversing the numerous degrees of freedom in the IDP energy landscape, as well as force-fields that accurately model the protein and solvent interactions. In this review, we have provided an overview of the current state of computational methods for studying IDP structure and dynamics and discussed the major challenges faced in this field.

scholarly journals The mutational landscape of a prion-like domain

2019 ◽  
Author(s):  
Benedetta Bolognesi ◽  
Andre J. Faure ◽  
Mireia Seuma ◽  
Jörn M. Schmiedel ◽  
Gian Gaetano Tartaglia ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Rna Binding ◽  
Genetic Interactions ◽  
Disordered Proteins ◽  
Insoluble Protein ◽  
Cellular Toxicity ◽  
Intrinsically Disordered ◽  
Powerful Approach ◽  
Lateral Sclerosis

AbstractSpecific insoluble protein aggregates are the hallmarks of many neurodegenerative diseases1–5. For example, cytoplasmic aggregates of the RNA-binding protein TDP-43 are observed in 97% of cases of Amyotrophic Lateral Sclerosis (ALS)6,7. However, it is still unclear for ALS and other diseases whether it is the insoluble aggregates or other forms of the mutated proteins that cause these diseases that are actually toxic to cells8–13. Here we address this question for TDP-43 by systematically mutating14the protein and quantifying the effects on cellular toxicity. We generated >50,000 mutations in the intrinsically disordered prion-like domain (PRD) and observed that changes in hydrophobicity and aggregation potential are highly predictive of changes in toxicity. Surprisingly, however, increased hydrophobicity and cytoplasmic aggregation actually reduce cellular toxicity. Mutations have their strongest effects in a central region of the PRD, with variants that increase toxicity promoting the formation of more dynamic liquid-like condensates. The genetic interactions in double mutants reveal that specific structures exist in this ‘unstructured’ regionin vivo. Our results demonstrate that deep mutagenesis is a powerful approach for probing the sequence-function relationships of intrinsically disordered proteins as well as theirin vivostructural conformations. Moreover, we show that aggregation of TDP-43 is not harmful but actually protects cells, most likely by titrating the protein away from a toxic liquid-like phase.

scholarly journals A novel small molecule screening platform for disrupting toxic tau oligomers in cells

2019 ◽  
Author(s):  
Chih Hung Lo ◽  
Colin Kin-Wye Lim ◽  
Zhipeng Ding ◽  
Sanjula Wickramasinghe ◽  
Anthony R. Braun ◽  
...  
Keyword(s):  
Small Molecule ◽  
Intrinsically Disordered Proteins ◽  
Neuronal Cell ◽  
Disordered Proteins ◽  
Therapeutic Window ◽  
Lag Phase ◽  
Microtubule Binding ◽  
Intrinsically Disordered ◽  
Tau Oligomers ◽  
In Cells

AbstractTauopathies, including Alzheimer’s disease, are a group of neurodegenerative disorders characterized by pathological aggregation of the microtubule binding protein tau. Recent studies suggest that toxic tau oligomers, which are soluble and distinct from insoluble beta-sheet fibrils, are central players in neuronal cell death. To exploit this new therapeutic window, we engineered two first-in-class FRET based biosensors that monitor tau conformations in cells. Because this new technology platform operates in cells, it enables high-throughput screening of small molecules that target tau oligomers while avoiding the uncertainties of idiosyncratic in vitro preparations of tau assemblies from purified protein. We found a small molecule, MK-886, that disrupts tau oligomers and reduces tau-induced cell cytotoxicity with nanomolar potency. Using SPR and an advanced single-molecule FRET technique, we show that MK-886 directly binds to tau and specifically perturbs the folding of tau monomer in the proline-rich and microtubule-binding regions. Furthermore, we show that MK-886 accelerates the tau aggregation lag phase using a thioflavin-T assay, implying that the compound stabilizes a non-toxic, on-pathway oligomer. The technology described here should generalize to the study and targeting of conformational ensembles within the aggregation pathways of most intrinsically disordered proteins.

scholarly journals Mechanism of Small-Molecule Binding by Intrinsically Disordered Proteins

2010 ◽  
Vol 98 (3) ◽  
pp. 259a
Author(s):  
Steven J. Metallo ◽  
Ariele Viacava Follis ◽  
Dalia I. Hammoudeh ◽  
Edward V. Prochownik
Keyword(s):  
Small Molecule ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered

scholarly journals Molecular basis of small-molecule binding to α-synuclein

2021 ◽  
Author(s):  
Paul Robustelli ◽  
Alain Ibanez-de-Opakua ◽  
Cecily Campbell-Bezat ◽  
Fabrizio Giordanetto ◽  
Stefan Becker ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Rational Design ◽  
Intrinsically Disordered Proteins ◽  
Md Simulations ◽  
Structural Features ◽  
Atomic Level ◽  
Disordered Proteins ◽  
Structure Based Drug Design ◽  
Intrinsically Disordered

AbstractIntrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-timescale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson’s disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein, but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.

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