Discovery of Small-Molecule Degraders for Alpha-Synuclein Aggregates

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(12), P. 7926 - 7942

Published: June 2, 2023

Alpha-synuclein (αSyn) species, especially the oligomers and fibers, are associated with multiple neurodegenerative diseases cannot be directly targeted under conventional pharmacological paradigm. Proteolysis-targeting chimera technology confers degradation of various "undruggable" targets; however, hardly any small-molecule degrader for αSyn aggregates has been reported yet. Herein, by using probe molecule sery308 as a warhead, series degraders were designed synthesized. Their effects on evaluated modified pre-formed fibril-seeding cell model. Compound 2b exhibited highest efficiency (DC50 = 7.51 ± 0.53 μM) high selectivity. Mechanistic exploration revealed that both proteasomal lysosomal pathways involved in this kind degradation. Moreover, therapeutic tested SH-SY5Y (human neuroblastoma line) cells Caenorhabditis elegans. Our results provided new class candidates against synucleinopathies broadened substrate spectrum PROTAC-based degraders.

Language: Английский

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AdipoRon promotes amyloid‐β clearance through enhancing autophagy via nuclear GAPDH‐induced sirtuin 1 activation in Alzheimer's disease

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(17), P. 3039 - 3063

Published: April 28, 2024

Abstract Background and Purpose Amyloid‐ β (A ) peptide is one of the more important pathological markers in Alzheimer's disease (AD). The development AD impairs autophagy, which results an imbalanced clearance A . Our previous research demonstrated that AdipoRon, agonist adiponectin receptors, decreased deposition enhanced cognitive function AD. However, exact mechanisms by AdipoRon affects remain unclear. Experimental Approach We studied how autophagy HT22 cells APP/PS1 transgenic mice. also investigated signalling pathway involved used pharmacological inhibitors to examine role this process. Key Results promotes activating neuronal Interestingly, we found induces nuclear translocation GAPDH, where it interacts with SIRT1/DBC1 complex. This interaction then leads release DBC1 activation SIRT1, turn activates autophagy. Importantly, inhibiting either GAPDH or SIRT1 suppress activity counteracts elevated caused AdipoRon. suggests plays a critical effect on autophagic induction Conclusion Implications enhancing through AdipoR1/AMPK‐dependent subsequent SIRT1. novel molecular sheds light modulation may lead new therapeutic strategies targeting pathway.

Language: Английский

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Histone Deacetylases as Epigenetic Targets for Treating Parkinson’s Disease

Brain Sciences, Journal Year: 2022, Volume and Issue: 12(5), P. 672 - 672

Published: May 21, 2022

Parkinson’s disease (PD) is a chronic progressive neurodegenerative that increasingly becoming global threat to the health and life of elderly worldwide. Although there are some drugs clinically available for treating PD, these treatments can only alleviate symptoms PD patients but cannot completely cure disease. Therefore, exploring other potential mechanisms develop more effective modify course still highly desirable. Over last two decades, histone deacetylases, as an important group epigenetic targets, have attracted much attention in drug discovery. This review focused on current knowledge about deacetylases involved pathophysiology their inhibitors used studies. Further perspectives related small molecules inhibit or degrade treat were also discussed.

Language: Английский

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Harmol promotes α-synuclein degradation and improves motor impairment in Parkinson’s models via regulating autophagy-lysosome pathway

npj Parkinson s Disease, Journal Year: 2022, Volume and Issue: 8(1)

Published: Aug. 6, 2022

Abstract The abnormal accumulation of α-synuclein (α-syn) is a crucial factor for the onset and pathogenesis Parkinson’s disease (PD), autophagy-lysosome pathway (ALP) contributes to α-syn turnover. AMP-activated protein kinase (AMPK) mammalian target rapamycin (mTOR) regulate autophagy by initiating macroautophagy cascade promoting lysosomal biogenesis via increased transcription EB (TFEB) activity. Hence, activation AMPK-mTOR-TFEB axis-mediated might promote clearance in PD. Harmol β-carboline alkaloid that has been extensively studied variety diseases but rarely PD models. In this study, we aimed evaluate effect underlying mechanism harmol models vitro vivo. We show reduces ALP dose- time-dependent manner cell model overexpressed human A53T mutant α-syn. also demonstrate promotes translocation TFEB into nucleus accompanies restoration autophagic flux biogenesis. Importantly, improves motor impairment down-regulates levels substantia nigra prefrontal cortex transgenic mice model. Further studies revealed activate through clearance. These vivo improvements activates mediated pathway, resulting reduced α-syn, suggesting potential benefit treatment

Language: Английский

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Cardiomyocytic FoxP3 is involved in Parkin-mediated mitophagy during cardiac remodeling and the regulatory role of triptolide

Theranostics, Journal Year: 2022, Volume and Issue: 12(5), P. 2483 - 2501

Published: Jan. 1, 2022

Rationale: Forkhead/winged helix transcriptional factor P3 (FoxP3) is a well-studied transcription that maintains the activity of T cells, but whether cardiomyocytic FoxP3 participates in cardiac remodeling (CR) remains unclear.The present study was to investigate role CR from perspective mitophagy.Methods: induced by angiotensin II (AngII) vitro, or isoproterenol (Iso) vivo using male C57 mice DTR mice.Histological changes were observed hematoxylin-eosin and Masson staining.Molecular detected immunohistochemistry, immunofluorescence, immunoblotting, real-time PCR.Mitophagy shaped transmission electron microscopy co-localization.The mRNA expression operated siRNA adeno associated virus (AAV).Molecular interactions co-localization, immunoprecipitation (IP), chromatin IP.Results: The nuclear translocation downregulated CR, while they upregulated after triptolide (TP) treatment.In left ventricle (LV) mice, autophagy activated continuously myocardium, TP significantly attenuated it.AngII massive mitophagy characterized activation regulatory protein 5 (Atg5)-dependent autophagic flux.Critically, Parkin identified as main adaptor mediated myocardial responsible for effect TP.Moreover, downregulation inhibited AngII-induced mitophagy.We found increased inhibition treatment reversed completely FoxP3-deficient LVs.Mechanistically, interacted with motif located downstream activating 4 (ATF4)-binding involved promoter hijacked free ATF4 decrease CR.Conclusion: Cardiomyocytic could negatively regulate Parkin-mediated restoring provided cardioprotective strategy inhibiting excessive mitophagy.

Language: Английский

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