Dihydroquinazolines enhance 20S proteasome activity and induce degradation of α-synuclein, an intrinsically disordered protein associated with neurodegeneration

Fiolek, Taylor J; Magyar, Christina L.; Wall, Tyler; Davies, Steven B.; Campbell, Molly V.; Savich, Christopher J.; Tepe, Jetze J.; Mosey, Robert A.

doi:10.1016/j.bmcl.2021.127821

Cited by 19 publications

(13 citation statements)

References 61 publications

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“…Proteasome inhibition by small molecules is an anticancer strategy used for almost 20 years (59). To the contrary, specific proteasome activation is still at a preclinical stage, with promising but nevertheless limited reports concerning mostly the 20S core (44,(60)(61)(62)(63)(64). Recent notable examples include fluspirilene analogs that activate the 20S proteasome in vitro and prevent its inhibition by A oligomers (64).…”

Section: Discussionmentioning

confidence: 99%

Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s-like pathology in mouse and fly APP overexpression models

et al. 2022

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The proteasome has key roles in neuronal proteostasis, including the removal of misfolded and oxidized proteins, presynaptic protein turnover, and synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer’s disease (AD). We show that prevention of proteasome dysfunction by genetic manipulation delays mortality, cell death, and cognitive deficits in fly and cell culture AD models. We developed a transgenic mouse with neuronal-specific proteasome overexpression that, when crossed with an AD mouse model, showed reduced mortality and cognitive deficits. To establish translational relevance, we developed a set of TAT-based proteasome-activating peptidomimetics that stably penetrated the blood-brain barrier and enhanced 20 S /26 S proteasome activity. These agonists protected against cell death, cognitive decline, and mortality in cell culture, fly, and mouse AD models. The protective effects of proteasome overexpression appear to be driven, at least in part, by the proteasome’s increased turnover of the amyloid precursor protein along with the prevention of overall proteostatic dysfunction.

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Section: Discussionmentioning

confidence: 99%

Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s-like pathology in mouse and fly APP overexpression models

et al. 2022

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“…These soluble oligomeric forms are also responsible for impairing proteasome function, which further drives disease progression [ 94 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ]. Multiple studies have indicated that enhancing proteasome proteolytic activity prevents the accumulation of these IDPs, reduces brain damage and improves cognitive performance in mouse models, and may be a new therapeutic strategy to treat neurodegenerative diseases [ 8 , 68 , 69 , 70 , 72 , 119 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ]. More recently, it has been recognized that the 20S proteasome of the proteasome plays a critical role in maintaining proteostasis by the direct degradation of oxidatively damaged and highly disordered proteins [ 10 , 133 , 134 , 135 , 136 , 137 , 138 ].…”

Section: Proteasome Activity and Diseasesmentioning

confidence: 99%

“…Earlier this year, Mosey et al synthesized and evaluated several dihydroquinoline analogues as 20S proteasome enhancers [ 125 , 281 ]. In this study, they were able to identify several promising 20S activators with the most potent being dihydroquinazoline 18 ( Figure 10 , compound 23 ), doubling proteasome proteolytic activity at 1.3 µM (EC 200 1.3 μM).…”

Section: Small Molecule Enhancers Of 20s Proteasome Activitymentioning

confidence: 99%

Advances in Proteasome Enhancement by Small Molecules

George

Tepe

2021

Biomolecules

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The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. In this review, we discuss the structure of proteasome and how proteasome’s proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation.

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“…Relatively few allosteric small molecule stimulators of the 20S proteasome have been described so far. These are, among others, betulinic acid [ 11 ], chlorpromazine [ 12 ], dihydroquinazolines [ 13 ], and fluspirilene analogs [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Peptidomimetics Based on C-Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins

et al. 2022

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Degradation of misfolded, redundant and oxidatively damaged proteins constitutes one of the cellular processes which are influenced by the 20S proteasome. However, its activity is generally thought to decrease with age which leads to the gradual accumulation of abnormal proteins in cells and their subsequent aggregation. Therefore, increasing proteasomal degradation constitutes a promising strategy to delay the onset of various age-related diseases, including neurodegenerative disorders. In this study we designed and obtained a series of peptidomimetic stimulators of 20S comprising in their sequences the C-terminal fragment of Blm10 activator. Some of the compounds were capable of enhancing the degradation of natively unfolded and oxidatively damaged proteins, such as α-synuclein and enolase, whose applicability as proteasome substrates was evaluated by microscale thermophoresis (MST). Furthermore, they increased the ChT-L activity of the proteasome in HEK293T cell extracts. Our studies indicate that the 20S proteasome-mediated protein substrates hydrolysis may be selectively increased by peptide-based stimulators acting in an allosteric manner. These compounds, after further optimization, may have the potential to counteract proteasome impairment in patients suffering from age-related diseases.

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Dihydroquinazolines enhance 20S proteasome activity and induce degradation of α-synuclein, an intrinsically disordered protein associated with neurodegeneration

Cited by 19 publications

References 61 publications

Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s-like pathology in mouse and fly APP overexpression models

Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s-like pathology in mouse and fly APP overexpression models

Advances in Proteasome Enhancement by Small Molecules

Peptidomimetics Based on C-Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins

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