The small aromatic compound SynuClean-D inhibits the aggregation and seeded polymerization of multiple α-synuclein strains

Peña-Díaz, Samuel; Pujols, Jordi; Vasili, Eftychia; Pinheiro, Francisca; Santos, Jaime; Manglano-Artuñedo, Zoe; Outeiro, Tiago F.; Ventura, Salvador

doi:10.1016/j.jbc.2022.101902

Cited by 10 publications

(10 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although both results may seem to be contradictory, they are, in fact, complementary. As reported in several studies [ 117 , 177 , 178 ], the presence of salt during the aggregation process compensates for the electrostatic repulsions exerted by the C -terminal region, thus precluding the anti-aggregational effect of this region and accelerating protein aggregation. Nevertheless, the fibrils obtained in the presence of salt presented a higher level of compaction than the ones formed in its absence do, which has been suggested to result from the hiding of the C-terminal acidic domain, which is normally exposed and forms a fuzzy coat.…”

Section: Alpha-synucleinmentioning

confidence: 98%

“…When this region is exposed at the PFFs surface, it has been reported to promote the amyloid aggregation of α-Syn either in vitro or in cellular models. In these cellular models, the C -terminus facilitates PFFs internalization by interacting with cell surface receptors [ 117 , 177 , 178 ]. Accordingly, and as for human prion proteins [ 179 , 180 ], α-Syn fibrils formed under different solution conditions share a common cross-β fold, but exhibit different conformation, seeding activity, neurotoxicity, and spreading in cells and when they are inoculated in rat brains [ 177 , 181 , 182 , 183 , 184 , 185 ].…”

Section: Alpha-synucleinmentioning

confidence: 99%

See 1 more Smart Citation

Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

2023

Self Cite

View full text Add to dashboard Cite

Parkinson’s disease, the second most common neurodegenerative disorder worldwide, is characterized by the accumulation of protein deposits in the dopaminergic neurons. These deposits are primarily composed of aggregated forms of α-Synuclein (α-Syn). Despite the extensive research on this disease, only symptomatic treatments are currently available. However, in recent years, several compounds, mainly of an aromatic character, targeting α-Syn self-assembly and amyloid formation have been identified. These compounds, discovered by different approaches, are chemically diverse and exhibit a plethora of mechanisms of action. This work aims to provide a historical overview of the physiopathology and molecular aspects associated with Parkinson’s disease and the current trends in small compound development to target α-Syn aggregation. Although these molecules are still under development, they constitute an important step toward discovering effective anti-aggregational therapies for Parkinson’s disease.

show abstract

Section: Alpha-synucleinmentioning

confidence: 98%

Section: Alpha-synucleinmentioning

confidence: 99%

Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…The currently studied aromatic compound SynuClean-D, which is 2-hydroxy-5-nitro-6-(3-nitrophenyl)-4-(trifluoromethyl)nicotinonitrile, has been shown to inhibit WT and PD-associated mutants H50Q and A30P, and also destroy newly formed amyloid fibrils [ 150 ]. In subsequent work, SynuClean-D showed the ability to reduce the accumulation of α-synuclein phosphorylated aggregates [ 151 ].…”

Section: Influence Of Various Molecules On the Aggregation Processmentioning

confidence: 99%

The Strategies of Development of New Non-Toxic Inhibitors of Amyloid Formation

Galzitskaya

Grishin

Glyakina

et al. 2023

IJMS

View full text Add to dashboard Cite

In recent years, due to the aging of the population and the development of diagnostic medicine, the number of identified diseases associated with the accumulation of amyloid proteins has increased. Some of these proteins are known to cause a number of degenerative diseases in humans, such as amyloid-beta (Aβ) in Alzheimer’s disease (AD), α-synuclein in Parkinson’s disease (PD), and insulin and its analogues in insulin-derived amyloidosis. In this regard, it is important to develop strategies for the search and development of effective inhibitors of amyloid formation. Many studies have been carried out aimed at elucidating the mechanisms of amyloid aggregation of proteins and peptides. This review focuses on three amyloidogenic peptides and proteins—Aβ, α-synuclein, and insulin—for which we will consider amyloid fibril formation mechanisms and analyze existing and prospective strategies for the development of effective and non-toxic inhibitors of amyloid formation. The development of non-toxic inhibitors of amyloid will allow them to be used more effectively for the treatment of diseases associated with amyloid.

show abstract

“…By a recently established fast, high-throughput α-Syn anti-aggregation screening method, Pujols et al [ 211 ] screened 14,400 compounds from the Maybridge HitFinder Collection, seeking putative α-Syn aggregation inhibitors. They identified a small aromatic molecule, SynuClean-D (2-hydroxy-5- nitro-6-(3-nitrophenyl)-4-(trifluoromethyl)nicotinonitril), that targets the NAC region within the α-Syn fibril core (detected by molecular docking and simulations) [ 190 , 212 ]. NMR studies confirmed no interaction between SynuClean-D and monomeric α-Syn.…”

Section: Therapies and Strategies Against Pd Related To α-Synmentioning

confidence: 99%

“…At the same time, based on its potential to disassemble amyloid fibrils, SynuClean-D exhibited protective and nontoxic effects on dopaminergic neurons and in C. elegans [ 211 ]. Very recently, SynuClean-D has shown disaggregation activity on different α-Syn amyloid polymorphs found in different synucleinopathies and disease progression stages [ 212 ]. Furthermore, SynuClean-D’s activity is based on conformation-dependent interactions.…”

Section: Therapies and Strategies Against Pd Related To α-Synmentioning

confidence: 99%

Alpha-Synuclein Aggregation Pathway in Parkinson’s Disease: Current Status and Novel Therapeutic Approaches

Vidović

Rikalović

2022

Cells

View full text Add to dashboard Cite

Following Alzheimer’s, Parkinson’s disease (PD) is the second-most common neurodegenerative disorder, sharing an unclear pathophysiology, a multifactorial profile, and massive social costs worldwide. Despite this, no disease-modifying therapy is available. PD is tightly associated with α-synuclein (α-Syn) deposits, which become organised into insoluble, amyloid fibrils. As a typical intrinsically disordered protein, α-Syn adopts a monomeric, random coil conformation in an aqueous solution, while its interaction with lipid membranes drives the transition of the molecule part into an α-helical structure. The central unstructured region of α-Syn is involved in fibril formation by converting to well-defined, β-sheet rich secondary structures. Presently, most therapeutic strategies against PD are focused on designing small molecules, peptides, and peptidomimetics that can directly target α-Syn and its aggregation pathway. Other approaches include gene silencing, cell transplantation, stimulation of intracellular clearance with autophagy promoters, and degradation pathways based on immunotherapy of amyloid fibrils. In the present review, we sum marise the current advances related to α-Syn aggregation/neurotoxicity. These findings present a valuable arsenal for the further development of efficient, nontoxic, and non-invasive therapeutic protocols for disease-modifying therapy that tackles disease onset and progression in the future.

show abstract

The small aromatic compound SynuClean-D inhibits the aggregation and seeded polymerization of multiple α-synuclein strains

Cited by 10 publications

References 56 publications

Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

The Strategies of Development of New Non-Toxic Inhibitors of Amyloid Formation

Alpha-Synuclein Aggregation Pathway in Parkinson’s Disease: Current Status and Novel Therapeutic Approaches

Contact Info

Product

Resources

About