An integrated bacterial system for the discovery of chemical rescuers of disease-associated protein misfolding

Matis, Ilias; Delivoria, Dafni Chrysanthi; Mavroidi, Barbara; Papaevgeniou, Nikoletta; Panoutsou, Stefania; Bellou, Stamatia; Papavasileiou, Konstantinos D.; Linardaki, Zacharoula I.; Stavropoulou, Alexandra; Vekrellis, Kostas; Boukos, N.; Kolisis, Fragiskos N.; Gonos, Efstathios S.; Margarity, Marigoula; Παπαδόπουλος, Μάνθος Γ.; Efthimiopoulos, Spiros; Pelecanou, Maria; Chondrogianni, Niki; Σκρέτας, Γεώργιος

doi:10.1038/s41551-017-0144-3

Cited by 25 publications

(45 citation statements)

References 63 publications

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“…The aggregation spectra of plain Aβ40 show at day 0 the typical random coil peak (negative maximum at 198 nm) the intensity of which gradually decreases as the peptide forms β–sheet structures (negative maximum at 222 nm, day 15) that further aggregate to higher order polymeric fibrils. The precipitation of the insoluble fibrils from solution eventually results in the loss of CD signal (days 30 and 40) [66]. As can be seen in Figure 8, the presence in the Aβ40 solution of intermediate bis- ethers di and dvi, apart from a noted delay in the overall process, did not significantly change the fibrillization course of Aβ40, and the CD signal almost reached baseline at day 40.…”

Section: Resultsmentioning

confidence: 99%

Small Multitarget Molecules Incorporating the Enone Moiety

et al. 2019

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Chalcones represent a class of small drug/druglike molecules with different and multitarget biological activities. Small multi-target drugs have attracted considerable interest in the last decade due their advantages in the treatment of complex and multifactorial diseases, since “one drug-one target” therapies have failed in many cases to demonstrate clinical efficacy. In this context, we designed and synthesized potential new small multi-target agents with lipoxygenase (LOX), acetyl cholinesterase (AChE) and lipid peroxidation inhibitory activities, as well as antioxidant activity based on 2-/4- hydroxy-chalcones and the bis-etherified bis-chalcone skeleton. Furthermore, the synthesized molecules were evaluated for their cytotoxicity. Simple chalcone b4 presents significant inhibitory activity against the 15-human LOX with an IC50 value 9.5 µM, interesting anti-AChE activity, and anti-lipid peroxidation behavior. Bis-etherified chalcone c12 is the most potent inhibitor of AChE within the bis-etherified bis-chalcones followed by c11. Bis-chalcones c11 and c12 were found to combine anti-LOX, anti-AchE, and anti-lipid peroxidation activities. It seems that the anti-lipid peroxidation activity supports the anti-LOX activity for the significantly active bis-chalcones. Our circular dichroism (CD) study identified two structures capable of interfering with the aggregation process of Aβ. Compounds c2 and c4 display additional protective actions against Alzheimer’s disease (AD) and add to the pleiotropic profile of the chalcone derivatives. Predicted results indicate that the majority of the compounds with the exception of c11 (144 Å) can cross the Blood Brain Barrier (BBB) and act in CNS. The results led us to propose new leads and to conclude that the presence of a double enone group supports better biological activities.

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Section: Resultsmentioning

confidence: 99%

Small Multitarget Molecules Incorporating the Enone Moiety

et al. 2019

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“…The system can also be utilized to discover inhibitors of protein dimerization like the cyclic peptide inhibitors found to prevent the homodimerization of IDOL E3 ubiquitin ligase with a K D of 4.6 µM (Leitch et al, 2018) and BCL6 with a K D of 142 µM (Osher et al, 2018). In addition, even correctors of protein misfolding can be identified using SICLOPPS-based screening (Matis et al, 2017).…”

Section: Protein Splicing Methodsmentioning

confidence: 99%

Methodologies for Backbone Macrocyclic Peptide Synthesis Compatible With Screening Technologies

et al. 2020

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Backbone macrocyclic structures are often found in diverse bioactive peptides and contribute to greater conformational rigidity, peptidase resistance, and potential membrane permeability compared to their linear counterparts. Therefore, such peptide scaffolds are an attractive platform for drug-discovery endeavors. Recent advances in synthetic methods for backbone macrocyclic peptides have enabled the discovery of novel peptide drug candidates against diverse targets. Here, we overview recent technical advancements in the synthetic methods including 1) enzymatic synthesis, 2) chemical synthesis, 3) split-intein circular ligation of peptides and proteins (SICLOPPS), and 4) in vitro translation system combined with genetic code reprogramming. We also discuss screening methodologies compatible with those synthetic methodologies, such as one-beads one-compound (OBOC) screening compatible with the synthetic method 2, cell-based assay compatible with 3, limiting-dilution PCR and mRNA display compatible with 4.

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“…Furthermore,w ee valuated the detox effect of PPV-NP under physiologically relevant conditions by using PC12 cells as the neuronal model. [40,41] This process motivated the internalization of b-sheet-rich structures and finally resulted in metabolic disorders and cell death. Thec ell viability after incubation with Ab42 oligomers is shown in Figure 4d.A b42 exhibited ah igh toxicity for PC12 cells.…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies have demonstrated that the binding of aggregated Ab species to ap lasma membrane initiated Ab-induced cytotoxicity. [40,41] This process motivated the internalization of b-sheet-rich structures and finally resulted in metabolic disorders and cell death. To investigate the mechanism of detox effect of PPV-NP,immunocytochemistry was conducted to assess the impact of PPV-NP on the binding of Ab42 to PC12 cell surfaces.P C12 cells with Ab42 aggregates showed marked reactivity with 6E10 ( Figure 4e), and indicated the attachment of Ab42 aggregates to PC12 cell membranes.W hile for the group in the presence of PPV-NP, slight 6E10 staining was observed.…”

Section: Methodsmentioning

confidence: 99%

Reactive Amphiphilic Conjugated Polymers for Inhibiting Amyloid β Assembly

Sun

Liu

et al. 2019

Angew Chem Int Ed

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Protein misfolding and aberrant aggregations are associated with multiple prevalent and intractable diseases. Inhibition of amyloid assembly is apromising strategy for the treatment of amyloidosis.R eported here is the design and synthesis of areactive conjugated polymer,apoly(p-phenylene vinylene) derivative,f unctionalizedw ith p-nitrophenyl esters (PPV-NP) and it inhibits the assembly of amyloid proteins, degrades preformed fibrils,a nd reduces the cytotoxicity of amyloid aggregations in living cells.PPV-NP is attached to the proteins through hydrophobic interactions and irreversible covalent linkage.P PV-NP also exhibited the capacity to eliminate Ab plaques in brain slices in ex vivo assays.T his work represents an innovative attempt to inhibit protein pathogenic aggregates,and may offer insights into the development of therapeutic strategies for amyloidosis.Proteins are one of the most important basic bio-macromolecules in organisms.T he aberrant assembly of proteins into insoluble amyloid aggregates would disrupt their biological functions and result in the generation of toxic intermediates and amyloidosis,w hich are relevant to ar ange of intractable human disorders such as Alzheimersd isease, Parkinsonsd isease,d ialysis-related amyloidosis,a nd type-2 diabetes. [1][2][3][4][5][6][7] On this account, numerous approaches to inhibit amyloid assembly have emerged, ranging from synthetic and natural small-molecule compounds, [4,8,9] peptides, [10,11] antibodies, [12] and nanoparticles [13,14] to artificial chaperones, [15] which make certain achievements to the inhibition of pathogenic aggregates.H owever,t od ate,t he pharmacological treatments for these diseases are still unsatisfactory. [16] Rational chemical designs to effectively inhibit and disrupt the amyloid assembly are still of great significance.In fact, most previous inhibitors functioned through noncovalent interactions,s uch as hydrophobic interactions, p-p stacking,e lectrostatic interactions,a nd hydrogen bonding. These interactions are intrinsically weak and susceptible to the surrounding environment. [17] Thef luctuation of either pH or temperature may induce the disassembly of inhibitor/ protein complexes,and would make the inhibitors invalid. In contrast, covalent interactions are more chemically stable and not susceptible to the fluctuation of surrounding environment. Reactions between inhibitors and proteins are usually irreversible,and inhibitors could remain attached to proteins for long time.T hus,d eveloping new inhibiting materials for amyloid assembly with acovalent-linking strategy is expected to lead to prolonged duration of inhibition and improved efficiency.T he amphiphilic conjugated polymers are considered pioneering materials in the biomedical field owing to their unique photoelectrical properties. [18][19][20][21][22][23][24] Here,w e designed and synthesized ar eactive conjugated polymer, ap oly(p-phenylene vinylene) derivative,f unctionalized with p-nitrophenyl active esters (PPV-NP) to inhibit protein assembly and disru...

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An integrated bacterial system for the discovery of chemical rescuers of disease-associated protein misfolding

Cited by 25 publications

References 63 publications

Small Multitarget Molecules Incorporating the Enone Moiety

Small Multitarget Molecules Incorporating the Enone Moiety

Methodologies for Backbone Macrocyclic Peptide Synthesis Compatible With Screening Technologies

Reactive Amphiphilic Conjugated Polymers for Inhibiting Amyloid β Assembly

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