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 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 Enhancing c-MYC degradation via 20S proteasome activation induces in vivo anti-tumor efficacy

2020 ◽  
Author(s):  
Evert Njomen ◽  
Theresa A. Lansdell ◽  
Allison Vanecek ◽  
Vanessa Benham ◽  
Matt P. Bernard ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Target Genes ◽  
Intrinsically Disordered Proteins ◽  
Therapeutic Potential ◽  
Human Cancer ◽  
Disordered Proteins ◽  
20S Proteasome ◽  
Intrinsically Disordered

SUMMARYEnhancing proteasome activity is a potential new therapeutic strategy to prevent the accumulation of aberrant high levels of protein that drive the pathogenesis of many diseases. Herein, we examine the use of small molecules to activate the 20S proteasome to reduce aberrant signaling by the undruggable oncoprotein c-MYC, to treat c-MYC driven oncogenesis. Overexpression of c-MYC is found in more than 50% of all human cancer but remains undruggable because of its highly dynamic intrinsically disordered 3-D conformation, which renders traditional therapeutic strategies largely ineffective. We demonstrate herein that small molecule activation of the 20S proteasome targets dysregulated intrinsically disordered proteins (IDPs), including c-MYC, and reduces cancer growth in vitro and in vivo models of multiple myeloma, and is even effective in bortezomib resistant cells and unresponsive patient samples. Genomic analysis of various cancer pathways showed that proteasome activation results in downregulation of many c-MYC target genes. Moreover, proteasome enhancement was well tolerated in mice and dogs. These data support the therapeutic potential of 20S proteasome activation in targeting IDP-driven proteotoxic disorders, including cancer, and demonstrate that this new therapeutic strategy is well tolerated in vivo.

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 Ubiquitin-independent protein degradation in proteasomes

2018 ◽  
Vol 64 (2) ◽  
pp. 134-148 ◽  
Author(s):  
O.A. Buneeva ◽  
A.E. Medvedev
Keyword(s):  
Protein Degradation ◽  
Mammalian Cells ◽  
Intrinsically Disordered Proteins ◽  
Amino Acid Sequences ◽  
Disordered Proteins ◽  
20S Proteasome ◽  
Independent Manner ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Independent Protein

Proteasomes are large supramolecular protein complexes present in all prokaryotic and eukaryotic cells, where they perform targeted degradation of intracellular proteins. Until recently, it was generally accepted that prior proteolytic degradation in proteasomes the proteins had to be targeted by ubiquitination: the ATP-dependent addition of (typically four sequential) residues of the low-molecular ubiquitin protein, involving the ubiquitin-activating enzyme, ubiquitin-conjugating enzyme and ubiquitin ligase. The cytoplasm and nucleoplasm proteins labeled in this way are then digested in 26S proteasomes. However, in recent years it has become increasingly clear that using this route the cell eliminates only a part of unwanted proteins. Many proteins can be cleaved by the 20S proteasome in an ATP-independent manner and without previous ubiquitination. Ubiquitin-independent protein degradation in proteasomes is a relatively new area of studies of the role of the ubiquitin-proteasome system. However, recent data obtained in this direction already correct existing concepts about proteasomal degradation of proteins and its regulation. Ubiquitin-independent proteasome degradation needs the main structural precondition in proteins: the presence of unstructured regions in the amino acid sequences that provide interaction with the proteasome. Taking into consideration that in humans almost half of all genes encode proteins that contain a certain proportion of intrinsically disordered regions, it appears that the list of proteins undergoing ubiquitin-independent degradation will demonstrate further increase. Since 26S of proteasomes account for only 30% of the total proteasome content in mammalian cells, most of the proteasomes exist in the form of 20S complexes. The latter suggests that ubiquitin-independent proteolysis performed by the 20S proteasome is a natural process of removing damaged proteins from the cell and maintaining a constant level of intrinsically disordered proteins. In this case, the functional overload of proteasomes in aging and/or other types of pathological processes, if it is not accompanied by triggering more radical mechanisms for the elimination of damaged proteins, organelles and whole cells, has the most serious consequences for the whole organism.

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

Thermo-resistant intrinsically disordered proteins are efficient 20S proteasome substrates

2012 ◽  
Vol 8 (1) ◽  
pp. 368-373 ◽  
Author(s):  
Peter Tsvetkov ◽  
Nadav Myers ◽  
Oren Moscovitz ◽  
Michal Sharon ◽  
Jaime Prilusky ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
20S Proteasome ◽  
Intrinsically Disordered
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