Ageing Research Reviews, Journal Year: 2024, Volume and Issue: unknown, P. 102584 - 102584
Published: Nov. 1, 2024
Language: Английский
Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(5), P. 3448 - 3466
Published: Feb. 15, 2024
The aggregation of specific proteins is a histopathological hallmark in various neurodegenerative diseases (NDs), among which Alpha-synuclein (α-Syn) and tau have received increased attention. targeted protein degradation (TPD) strategy has been studied the treatment NDs, but multitarget bifunctional molecules ignored. Herein, series effective dual PROTAC degraders were developed, could degrade α-Syn aggregates total simultaneously. effects evaluated vitro, results showed that T3 significantly knockdown efficiency with DC50 1.57 ± 0.55 4.09 0.90 μM, respectively. Further mechanistic exploration effect was mediated by ubiquitin–proteasome system (UPS). Additionally, therapeutic efficacy confirmed an MPTP-induced PD mouse model. Our suggest these PROTACs may provide potential for NDs.
Language: Английский
Citations
15
Neurotherapeutics, Journal Year: 2025, Volume and Issue: unknown, P. e00548 - e00548
Published: Feb. 1, 2025
Amyloidoses, which are characterized by abnormal accumulation of amyloid proteins leading to organ dysfunction, represent a major therapeutic challenge. They include neurodegenerative diseases, such as Alzheimer disease (AD), tauopathies and synucleinopathies. Since amyloids causative factors in these the importance proteolytic methods remove amyloid, immunotherapy Proteolysis Targeting Chimera (PROTAC) technology, has been recognized. Immunotherapy removes target antibody-mediated reactions is most studied method practical use for treatment AD. PROTAC small molecule that uses ubiquitin-proteasome system degrade intracellular demonstrated efficacy clinical trials other diseases. In addition, new modality called photo-oxygenation developed. Photo-oxygenation selectively adding oxygen using photocatalyst, compound activated light. Studies both vitro vivo have shown promising results inhibiting aggregation enhancing clearance proteins. this review, we introduce discuss modalities, provide insights into potential future directions application amyloidoses.
Language: Английский
Citations
1
Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 147, P. 107386 - 107386
Published: April 18, 2024
Language: Английский
Citations
8
European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 267, P. 116168 - 116168
Published: Feb. 1, 2024
Language: Английский
Citations
5
Future Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 15
Published: Feb. 11, 2025
Neurodegenerative diseases are characterized by impairments in movement and cognitive functions. These disorders frequently associated with the accumulation of misfolded protein aggregates, which present significant challenges for treatment conventional small-molecule inhibitors. While FDA-approved amyloid-beta-directed antibodies, such as Lecanemab, have recently shown clinical success modifying disease progression, there currently no treatments capable curing neurodegenerative diseases. Emerging technologies like proteolysis-targeting chimeras (PROTACs) offer additional promise targeting disease-causing proteins degradation, potentially opening new therapeutic avenues. Recent experiments demonstrated that PROTACs can specifically target degrade pathogenic diseases, thereby offering potential This review discusses latest advances employing treating delves into opportunities. Our goal is to provide researchers drug development insights on creating novel applications.
Language: Английский
Citations
0
Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown
Published: March 25, 2025
Language: Английский
Citations
0
Acta Pharmacologica Sinica, Journal Year: 2025, Volume and Issue: unknown
Published: April 7, 2025
Language: Английский
Citations
0
The Chemical Record, Journal Year: 2023, Volume and Issue: 24(2)
Published: Nov. 2, 2023
Parkinson's disease is a yet incurable, age-related neurodegenerative disorder characterized by the aggregation of small neuronal protein α-synuclein into amyloid fibrils. Inhibition this process prospective strategy for developing disease-modifying treatment. We overview here molecule, peptide, and inhibitors fibrillization reported to date. Special attention was paid specificity critical analysis their action mechanisms. Namely, importance oxidation polyphenols cross-linking inhibitory dimers highlighted. also compared strategies targeting monomeric, oligomeric, fibrillar species, thoroughly discussed strong weak sides different approaches testing inhibitors.
Language: Английский
Citations
7
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown
Published: March 13, 2024
Abstract Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation α-synuclein (α-syn) in brain, leading to motor and neuropsychiatric symptoms. Currently, there no known cures for synucleinopathies, treatments mainly focus on symptom management. In this study, we developed single-domain antibody (sdAb)-based protein degrader with features designed enhance proteasomal degradation α-syn. This sdAb derivative targets both α-syn Cereblon (CRBN), substrate-receptor E3-ubiquitin ligase CRL4 CRBN , thereby induces ubiquitination degradation. Our results indicate that therapeutic candidate enhances α-syn, addition endogenous lysosomal machinery. By promoting improved clearance primary culture mouse models synucleinopathy. These findings our sdAb-based is promising synucleinopathies. Considering only small percentage antibodies enter more potent sdAbs greater brain entry than whole could clinical benefits antibody-based therapies.
Language: Английский
Citations
2
Cells, Journal Year: 2024, Volume and Issue: 13(4), P. 338 - 338
Published: Feb. 14, 2024
Neurological disorders such as Parkinsonism cause serious socio-economic problems there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner SYN, termed Tubulin Polymerization Promoting Protein (TPPP), which has important physiological and pathological activities regulation microtubule network promotion SYN aggregation. role TPPP often neglected research, we here attempt to remedy. In normal brain, are expressed endogenously neurons oligodendrocytes, respectively, whilst, an early stage Parkinsonism, soluble hetero-associations these proteins found both cell types. cell-to-cell transmission proteins, central disease progression, provides unique situation for specific drug targeting. Different strategies intervention discovery biomarkers include (i) interface targeting SYN-TPPP hetero-complex; (ii) proteolytic degradation and/or using PROTAC technology; (iii) depletion by miRNA technology. also discuss potential roles phenotype stabilization oligodendrocytes.
Language: Английский
Citations
1