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 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

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 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.

scholarly journals Small Molecule Enhancement of 20S Proteasome Activity Targets Intrinsically Disordered Proteins

2017 ◽  
Vol 12 (9) ◽  
pp. 2240-2247 ◽  
Author(s):  
Corey L. Jones ◽  
Evert Njomen ◽  
Benita Sjögren ◽  
Thomas S. Dexheimer ◽  
Jetze J. Tepe
Keyword(s):  
Small Molecule ◽  
Intrinsically Disordered Proteins ◽  
Proteasome Activity ◽  
Disordered Proteins ◽  
20S Proteasome ◽  
Intrinsically Disordered

scholarly journals A small molecule stabilises the disordered native state of the Alzheimer's Aβ peptide

2021 ◽  
Author(s):  
Thomas Löhr ◽  
Kai Kohlhoff ◽  
Gabriella T. Heller ◽  
Carlo Camilloni ◽  
Michele Vendruscolo
Keyword(s):  
Small Molecule ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Binding Mechanism ◽  
Native State ◽  
Dynamic Binding ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Aβ42 Peptide

The stabilisation of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here we report a small molecule that stabilises the native state of the Aβ42 peptide, an intrinsically disordered protein fragment associated with Alzheimer's disease. We show that this stabilisation takes place by a dynamic binding mechanism, in which both the small molecule and the Aβ42 peptide remain disordered. This disordered binding mechanism involves enthalpically favourable local π-stacking interactions coupled with entropically advantageous global effects. These results indicate that small molecules can stabilise disordered proteins in their native states through transient non-specific interactions that provide enthalpic gain while simultaneously increasing the conformational entropy of the proteins.

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.

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