Combinatorial Synthesis of Structurally Diverse Triazole-Bridged Flavonoid Dimers and Trimers

Sum, Tze Han; Galloway, Warren R. J. D.; Collins, Súil; Twigg, David G.; Hollfelder, Florian; Spring, David R.

doi:10.3390/molecules21091230

Cited by 18 publications

(10 citation statements)

References 51 publications

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“…Synthetic Aβ42 and Aβ42 Hilyte™ Fluor 488 (both from Anaspec, Seraing, Belgium) were prepared as previously described ( 94 ). Briefly, lyophilized Aβ42 (1 mg) was dissolved in ice-cold TFA (200 ml), sonicated at 0 °C for 60 s and then lyophilized overnight.…”

Section: Methodsmentioning

confidence: 99%

Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

Lautenschläger

Wagner-Valladolid

Stephens

et al. 2020

Journal of Biological Chemistry

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Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson’s disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species (ROS), all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality-control pathways such as the ubiquitin–proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.

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Section: Methodsmentioning

confidence: 99%

Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

Lautenschläger

Wagner-Valladolid

Stephens

et al. 2020

Journal of Biological Chemistry

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“…The peptide was prepared as previously described. 30 Briefly, lyophilised Aβ42 (1 mg) was dissolved in ice cold trifluroacetic acid (200 mL), sonicated at 0 °C for 60 s, then lyophilised overnight.…”

Section: Methodsmentioning

confidence: 99%

A unifiedin vitrotoin vivofluorescence lifetime screening platform yields amyloid β aggregation inhibitors

Collins

Vliet

Gielen

et al. 2022

Preprint

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Inhibiting the aggregation of amyloid β (1-42) is a promising strategy for the development of disease-modifying Alzheimer's disease therapeutics. To date, however, no sufficiently efficacious inhibitors have been identified, despite the best efforts of over 200 advanced drug development campaigns. This failure can be attributed to limitations in current compound screening and in vivo validation assays. Here, we report an in vitro to in vivo screening platform based on the use of a fluorescence lifetime aggregation sensor. The microfluidic nanoFLIM assay developed circumvents issues that plague conventional assays, such as lack of reproducibility, high cost and artefactual false read-outs. The fluorescence lifetime sensor can also dynamically monitor peptide aggregation in cellular and Caenorhabditis elegans disease models, providing directly comparable aggregation kinetics, which is not achievable by any other method. The power of this unified system for accelerating hit-to-lead strategies, lowering attrition rates and expediting in vivo screening, was demonstrated with a pilot screening campaign of 445 compounds, revealing a new inhibitor that can inhibit amyloid β self-assembly in vitro as well as in cellular and whole organism disease models.

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“…The addition of alkyl chains is achieved through an SN2 reaction with alkyl halides. The 1,2,3-triazolebridged flavonoids can be accessed through an alkynyl ether via click chemistry reactions with azide functionalization (Sum et al, 2016). Additionally, Zou et al (2020) demonstrated that the presence of hydroxyl groups in the B-ring is critical for the antiviral activity of flavonoids (Zou et al, 2020).…”

Section: Structure: Activity Relationshipmentioning

confidence: 99%

Flavonoids as Molecules With Anti-Zika virus Activity

et al. 2021

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Zika virus (ZIKV) is an arthropod-born virus that is mainly transmitted to humans by mosquitoes of the genus Aedes spp. Since its first isolation in 1947, only a few human cases had been described until large outbreaks occurred on Yap Island (2007), French Polynesia (2013), and Brazil (2015). Most ZIKV-infected individuals are asymptomatic or present with a self-limiting disease and nonspecific symptoms such as fever, myalgia, and headache. However, in French Polynesia and Brazil, ZIKV outbreaks led to the diagnosis of congenital malformations and microcephaly in newborns and Guillain-Barré syndrome (GBS) in adults. These new clinical presentations raised concern from public health authorities and highlighted the need for anti-Zika treatments and vaccines to control the neurological damage caused by the virus. Despite many efforts in the search for an effective treatment, neither vaccines nor antiviral drugs have become available to control ZIKV infection and/or replication. Flavonoids, a class of natural compounds that are well-known for possessing several biological properties, have shown activity against different viruses. Additionally, the use of flavonoids in some countries as food supplements indicates that these molecules are nontoxic to humans. Thus, here, we summarize knowledge on the use of flavonoids as a source of anti-ZIKV molecules and discuss the gaps and challenges in this area before these compounds can be considered for further preclinical and clinical trials.

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Combinatorial Synthesis of Structurally Diverse Triazole-Bridged Flavonoid Dimers and Trimers

Cited by 18 publications

References 51 publications

Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

A unifiedin vitrotoin vivofluorescence lifetime screening platform yields amyloid β aggregation inhibitors

Flavonoids as Molecules With Anti-Zika virus Activity

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