Oleic amide derivatives as small molecule stimulators of the human proteasome's core particle

Halder, Saayak; Macatangay, Nathaniel J; Zerfas, Breanna L.; Salazar-Chaparro, Andres F; Trader, Darci J.

doi:10.1039/d2md00133k

Cited by 3 publications

(9 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To have a more direct evidence supporting the protective role of proteasome activation in cortical neurons subjected to OGD, we used two oleic amide derivatives that were recently shown to act as 20S proteasome activators (Halder et al, 2022). Compound 17 (renamed to B12) and compound 25 (renamed to D3) were used to ascertain their protective effects in cultured neurons subjected to OGD, and were both shown to boost the activity of the 20S proteasome by 0.5 and 3.5-fold, respectively (Halder et al, 2022). Cerebrocortical neurons were pre-incubated with the compounds (10 µM) for 2 h prior to the insult and then exposed to 1.5 h of OGD.…”

Section: Resultsmentioning

confidence: 99%

“…The DUB USP14 inhibitor IU1 (20 µM; Focus Biomolecules) was added to the culture medium 30 min before OGD, or immediately after, and was present throughout the experiment. The 20S oleic derivatives B12 and D3 were synthesized as previously reported (Halder et al, 2022) and were added to the culture medium 2h before OGD (10 µM), and were present throughout the experiment incubated.…”

Section: Oxygen-glucose Deprivation (Ogd) Assaysmentioning

confidence: 99%

“…Both compounds blocked OGD-induced cell death as determined by analysis of the nuclear morphology (Figure 7A,B; ns p>0.05). Since B12 showed the highest efficacy in terms of increasing 20S proteasome activity (Halder et al, 2022), we sought to test its effect on calpain activation after OGD. Pre-incubation of the neurons with B12 also abrogated the effects of OGD on the activation of calpains, as determined by analysis of spectrin cleavage (Figure 7C; *pY 0.05).…”

Section: +mentioning

confidence: 99%

See 2 more Smart Citations

Activation of the 20S proteasome core particle prevents cell death induced by oxygen- and glucose deprivation in cultured cortical neurons

Salazar,

Curcio,

Mele

et al. 2024

Preprint

View full text Add to dashboard Cite

Neuronal damage in brain ischemia is characterized by a disassembly of the proteasome and a decrease in its activity. However, to what extent these alterations are coupled to neuronal death is controversial since proteasome inhibitors were shown to provide protection in different models of stroke in rodents. This question was addressed in the present work using cultured cerebrocortical neurons subjected to transient oxygen- and glucose-deprivation (OGD). Under the latter conditions there was a time-dependent loss in the proteasome activity, determined by cleavage of the Suc-LLVY-AMC fluorogenic substrate, and the disassembly of the proteasome, as assessed by native-polyacrylamide gel electrophoresis followed by western blot against Psma2 and Rpt6, which are components of the catalytic core and regulatory particle, respectively. Immunocytochemistry experiments against the two proteins also showed differential effects on their dendritic distribution. OGD also downregulated the protein levels of Rpt3 and Rpt10, two components of the regulatory particle, by a mechanism dependent on the activity of NMDA receptors and mediated by calpains. Activation of the proteasome activity, using an inhibitor USP14, a deubiquitinase enzyme, inhibited OGD-induced cell death, and decreased calpain activity as determined by analysis of spectrin cleavage. Similar results were obtained in the presence of two oleic amide derivatives (B12 and D3) which directly activate the 20S proteasome. Together, these results shown that calpain activation prevents neuronal death in cortical neurons subjected to OGD, suggesting that inhibition of the proteasome is a mediator of neuronal death in brain ischemia.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Oxygen-glucose Deprivation (Ogd) Assaysmentioning

confidence: 99%

Section: +mentioning

confidence: 99%

See 1 more Smart Citation

Activation of the 20S proteasome core particle prevents cell death induced by oxygen- and glucose deprivation in cultured cortical neurons

Salazar,

Curcio,

Mele

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Multiple small molecules and a handful of peptides (Figure 1B) have been observed to stimulate the proteasome. [8,[39][40][41][42][43] While these small molecules and peptides have been useful for answering foundational questions about the mechanism of proteasome stimulation, [39,40,44,45] the majority of proteasome stimulators reported to date either have low potency (e.g. AM-404 and ursolic acid), are not selective (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…For this reason, there is an effort to identify UIPS activators that can increase the rate of clearance of misfolded proteins. Multiple small molecules and a handful of peptides (Figure 1B) have been observed to stimulate the proteasome [8,39–43] . While these small molecules and peptides have been useful for answering foundational questions about the mechanism of proteasome stimulation, [39,40,44,45] the majority of proteasome stimulators reported to date either have low potency (e.g.…”

Section: Introductionmentioning

confidence: 99%

Discovery and Development of Cyclic Peptide Proteasome Stimulators

Nelson,

Harris,

Muli

et al. 2023

ChemBioChem

View full text Add to dashboard Cite

The proteasome degrades proteins, which is essential for cellular homeostasis. Ubiquitin independent proteolysis degrades highly disordered and misfolded proteins. A decline of proteasomal activity has been associated with multiple neurodegenerative diseases due to the accumulation of misfolded proteins. In this work, cyclic peptide proteasome stimulators (CyPPSs) that enhance the clearance of misfolded proteins were discovered. In the initial screen of predicted natural products (pNPs), several cyclic peptides were found to stimulate the 20S core particle (20S CP). Development of a robust structural activity relationship led to the identification of potent, cell permeable CyPPSs. In vitro assays revealed that CyPPSs stimulate degradation of highly disordered and misfolded proteins without affecting ordered proteins. Furthermore, using a novel flow‐based assay for proteasome activity, several CyPPSs were found to stimulate the 20S CP in cellulo. Overall, this work describes the development of CyPPSs as chemical tools capable of stimulating the proteasome and provides strong support for proteasome stimulation as a therapeutic strategy for neurodegenerative diseases.

show abstract

20S proteasome enhancers prevent cytotoxic tubulin polymerization-promoting protein induced α-synuclein aggregation

Staerz,

Anamoah,

Tepe

2024

iScience

View full text Add to dashboard Cite

Oleic amide derivatives as small molecule stimulators of the human proteasome's core particle

Abstract: A series of oleic acid amide derivatives were synthesized based on our previous and continuing endeavors towards stimulation of the 20S core particle of the proteasome (20S CP) with the...

Cited by 3 publications

References 16 publications

Activation of the 20S proteasome core particle prevents cell death induced by oxygen- and glucose deprivation in cultured cortical neurons

Activation of the 20S proteasome core particle prevents cell death induced by oxygen- and glucose deprivation in cultured cortical neurons

Discovery and Development of Cyclic Peptide Proteasome Stimulators

20S proteasome enhancers prevent cytotoxic tubulin polymerization-promoting protein induced α-synuclein aggregation

Contact Info

Product

Resources

About