Diphenyl triazine hybrids inhibit α-synuclein fibrillogenesis: Design, synthesis and in vitro efficacy studies

Maqbool, Mudasir; Gadhavi, Joshna; Hivare, Pravin; Gupta, Sharad; Hoda, Nasimul

doi:10.1016/j.ejmech.2020.112705

Cited by 9 publications

(11 citation statements)

References 38 publications

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“…Further, the protein was extracted via the osmotic shock lysis method described earlier and purified by Diethyl Amino Ethyl (DEAE) Sepharose using ion-exchange chromatography. 18 As shown in Figure 1A, the eluted fractions contain a single pure protein, as confirmed by the 15% SDS PAGE. This protein was identified as α-Syn by western blot using the H3C monoclonal antibody specific for α-Syn, which gave a single purified band at $15 kDa (Figure 1B).…”

Section: Purification Of α-Synuclein and Characterization Of α-Syn Pffsupporting

confidence: 56%

“…Recombinant human α‐Syn was expressed in Escherichia coli BL21 (DE3). Further, the protein was extracted via the osmotic shock lysis method described earlier and purified by Diethyl Amino Ethyl (DEAE) Sepharose using ion‐exchange chromatography 18 . As shown in Figure 1A, the eluted fractions contain a single pure protein, as confirmed by the 15% SDS PAGE.…”

Section: Resultsmentioning

confidence: 78%

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α‐Synuclein fibrils explore actin‐mediated macropinocytosis for cellular entry into model neuroblastoma neurons

Hivare

Gadhavi

Bhatia

et al. 2022

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Alpha‐synuclein (α‐Syn), an intrinsically disordered protein (IDP), is associated with neurodegenerative disorders, including Parkinson's disease (PD or other α‐synucleinopathies. Recent investigations propose the transmission of α‐Syn protein fibrils, in a prion‐like manner, by entering proximal cells to seed further fibrillization in PD. Despite the recent advances, the mechanisms by which extracellular protein aggregates internalize into the cells remain poorly understood. Using a simple cell‐based model of human neuroblastoma‐derived differentiated neurons, we present the cellular internalization of α‐Syn PFF to check cellular uptake and recycling kinetics along with the standard endocytic markers Transferrin (Tf) marking clathrin‐mediated endocytosis (CME) and Galectin3 (Gal3) marking clathrin‐independent endocytosis (CIE). Specific inhibition of endocytic pathways using chemical inhibitors reveals no significant involvement of CME, CIE and caveolae‐mediated endocytosis (CvME). A substantial reduction in cellular uptake was observed after perturbation of actin polymerization and treatment with macropinosomes inhibitor. Our results show that α‐Syn PFF mainly internalizes into the SH‐SY5Y cells and differentiated neurons via the macropinocytosis pathway. The elucidation of the molecular and cellular mechanism involved in the α‐Syn PFF internalization will help improve the understanding of α‐synucleinopathies including PD, and further design specific inhibitors for the same.

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Section: Purification Of α-Synuclein and Characterization Of α-Syn Pffsupporting

confidence: 56%

Section: Resultsmentioning

confidence: 78%

α‐Synuclein fibrils explore actin‐mediated macropinocytosis for cellular entry into model neuroblastoma neurons

Hivare

Gadhavi

Bhatia

et al. 2022

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“…Maqbool et al designed and synthesized a group of diphenyltriazine derivatives, among which some lower α-synuclein fibrillation by more than 50% and act as disaggregating agents in the in vitro thioflavin T (ThT) assay. Additionally, two of the obtained compounds, A4 and A8 ( 15a and 15b in Figure 2 ), seem to ameliorate cytotoxicity induced by the aggregation of α-synuclein [ 92 ]. Another team reported derivatives of 4-aminopyridine as neuroprotective agents.…”

Section: Recent Reports Of Novel Agents Against Parkinson’s Diseasementioning

confidence: 99%

Current Approaches and Tools Used in Drug Development against Parkinson’s Disease

et al. 2021

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Parkinson’s disease is a progressive neurodegenerative disorder characterized by the death of nerve cells in the substantia nigra of the brain. The treatment options for this disease are very limited as currently the treatment is mainly symptomatic, and the available drugs are not able to completely stop the progression of the disease but only to slow it down. There is still a need to search for new compounds with the most optimal pharmacological profile that would stop the rapidly progressing disease. An increasing understanding of Parkinson’s pathogenesis and the discovery of new molecular targets pave the way to develop new therapeutic agents. The use and selection of appropriate cell and animal models that better reflect pathogenic changes in the brain is a key aspect of the research. In addition, computer-assisted drug design methods are a promising approach to developing effective compounds with potential therapeutic effects. In light of the above, in this review, we present current approaches for developing new drugs for Parkinson’s disease.

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“…, and disaggregation of misfolded proteins, 22,23 i.e. , τ-protein, 24,25 amyloid-β (Aβ), 26,27 TAR DNA binding protein 43 (TDP-43), 28 α-synuclein, 29,30 etc. , using small therapeutic molecules.…”

Section: Introductionmentioning

confidence: 99%

“…However, effective treatments are desperately needed to support and improve the lives of people with dementia and their carers and families. As related to medicinal chemistry, several studies were reported on the development of new inhibitors of known biological targets related to neurodegenerative diseases, such as acetylcholinesterase (AChE), 16,17 butyrylcholinesterase (BuChE), 18 glycogen synthase kinase 3 beta (GSK3β), 19 monoamine oxidase A and B (MAO-A and MAO-B), 20 plasma membrane redox enzymes, 21 etc., and disaggregation of misfolded proteins, 22,23 i.e., τ-protein, 24,25 amyloid-β (Aβ), 26,27 TAR DNA binding protein 43 (TDP-43), 28 α-synuclein, 29,30 etc., using small therapeutic molecules. Most of the small molecules were synthesized using privileged scaffolds of medicinal importance such as pyrimidine, 31 pyrazine, 32 acridine, 33 triazolopyrimidine, 34,35 triazene, 36 coumarin, 37 chromones, etc.…”

Section: Introductionmentioning

confidence: 99%

Recent advancements in chromone as a privileged scaffold towards the development of small molecules for neurodegenerative therapeutics

et al. 2022

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Diphenyl triazine hybrids inhibit α-synuclein fibrillogenesis: Design, synthesis and in vitro efficacy studies

Cited by 9 publications

References 38 publications

α‐Synuclein fibrils explore actin‐mediated macropinocytosis for cellular entry into model neuroblastoma neurons

α‐Synuclein fibrils explore actin‐mediated macropinocytosis for cellular entry into model neuroblastoma neurons

Current Approaches and Tools Used in Drug Development against Parkinson’s Disease

Recent advancements in chromone as a privileged scaffold towards the development of small molecules for neurodegenerative therapeutics

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