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| Targets |
The primary molecular targets of NQTrp are the pathological aggregates of amyloid-β (Aβ) peptides, particularly Aβ1-42, and tau protein. NQTrp acts as a potent inhibitor of Aβ oligomerization and fibrillization, directly interfering with the nucleation-dependent polymerization process that drives amyloid formation. It completely inhibits Aβ oligomerization and fibrillization, thereby preventing the formation of the neurotoxic species responsible for synaptic impairment and neuronal cell death. Beyond Aβ, NQTrp also functions as an inhibitor of tau protein aggregation, demonstrating its generic anti-amyloidogenic effects across different amyloidogenic proteins. This dual targeting capability is particularly significant because both Aβ and tau pathologies are interconnected in the pathogenesis of Alzheimer's disease, with Aβ aggregation thought to accelerate tau pathology through various signaling cascades. By inhibiting the aggregation of both proteins, NQTrp addresses multiple nodes in the neurodegenerative cascade.
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| ln Vitro |
GDC6 peptide fibrils (50 μM) were observed in TEM examination when NQTrp was present in a 5:1, 1:1, or 1:5 ratio (GDC6: NQTrp). NQTrp blocks the production of elongated amyloid fibrils and, in a dose-dependent manner, efficiently suppresses fibrillation with GDC6 peptide (50 μM) [1]. NQTrp decreases the cytotoxicity caused by hexapeptide aggregates in ARPE-19 cells (IC50=70 μM) and has no harmful effects on retinal cell cultures [1].
In vitro, NQTrp exhibits exceptionally potent inhibitory activity against Aβ aggregation. It completely inhibits Aβ oligomerization and fibrillization, with an IC50 of 50 nM for the formation of fibrils from Aβ1-42, demonstrating its efficacy at nanomolar concentrations. This remarkable potency highlights the compound's high affinity for amyloidogenic intermediates and its ability to disrupt the assembly process at multiple stages. NQTrp significantly reduces the cytotoxicity induced by Aβ oligomers and increases cell viability in cultured neuronal cell lines. Furthermore, NQTrp effectively inhibits the fibrillation of the GDC6 peptide (50 μM) in a dose-dependent manner and prevents the formation of elongated amyloid fibrils. The compound also demonstrates activity against other amyloidogenic systems, such as full-length γD-crystallin, indicating its broad-spectrum anti-amyloidogenic potential. In ARPE-19 retinal pigment epithelial cells, NQTrp decreases the cytotoxicity induced by aggregates of the hexapeptide with an IC50 of 70 μM, further confirming its cytoprotective effects against aggregate-induced cell damage. |
| ln Vivo |
In vivo, NQTrp has demonstrated significant therapeutic efficacy in animal models of Alzheimer's disease. Notably, it significantly extends the lifespan of Drosophila melanogaster expressing human Aβ1-42, a well-established transgenic model for studying Aβ-induced neurotoxicity and Alzheimer's disease-related pathology. This lifespan extension provides compelling evidence that NQTrp can mitigate the deleterious effects of Aβ expression in a living organism, suggesting that it can cross biological barriers and engage its targets in the nervous system. Complete phenotypic recovery of an Alzheimer's disease model has been demonstrated through the use of this quinone-tryptophan hybrid aggregation inhibitor. The compound's ability to rescue behavioral and physiological deficits in vivo supports its potential as a disease-modifying therapeutic for Alzheimer's disease, rather than merely a symptomatic treatment. These in vivo findings are particularly encouraging because they demonstrate that inhibiting protein aggregation can translate into meaningful functional improvements and extended survival in a whole-organism context.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for NQTrp are not conventional enzyme inhibition studies, as the compound does not target a catalytic enzyme but rather interferes with protein-protein interactions involved in amyloid aggregation. Instead, the primary biochemical assay involves monitoring Aβ fibrillization using thioflavin T (ThT) fluorescence, a widely employed method that detects the formation of amyloid fibrils through enhanced fluorescence upon binding to β-sheet-rich structures. In these assays, Aβ1-42 peptide is incubated with varying concentrations of NQTrp, and the kinetics of fibril formation are monitored over time. The IC50 of 50 nM is determined from the dose-dependent inhibition of ThT fluorescence. Oligomerization is typically assessed using methods such as photo-induced cross-linking of unmodified proteins (PICUP), size-exclusion chromatography, or native gel electrophoresis, which can distinguish between monomeric, oligomeric, and fibrillar species. Additional biophysical techniques such as circular dichroism (CD) spectroscopy and Fourier-transform infrared (FTIR) spectroscopy can be employed to confirm the compound's ability to maintain proteins in their native conformation and prevent the transition to β-sheet-rich amyloid structures.
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| Cell Assay |
In vitro cellular assays for NQTrp are conducted using cultured neuronal cell lines, such as primary hippocampal neurons or established neuronal cell lines like SH-SY5Y or PC12 cells. In these assays, cells are exposed to pre-formed Aβ oligomers or fibrils in the presence or absence of varying concentrations of NQTrp, and cell viability is assessed using standard metabolic assays such as MTT or resazurin reduction. The compound's ability to reduce Aβ-induced cytotoxicity is quantified by measuring the percentage of viable cells relative to untreated controls. Additionally, cellular assays can assess the compound's effects on oxidative stress markers, mitochondrial membrane potential, and apoptotic signaling pathways, providing mechanistic insights into its neuroprotective actions. In ARPE-19 cells, NQTrp reduces the cytotoxicity induced by aggregates of the hexapeptide (41GCWMLY46) with an IC50 of 70 μM. These assays confirm that NQTrp not only prevents aggregation in cell-free systems but also protects living cells from the toxic effects of pre-formed aggregates, a critical feature for a therapeutic agent intended to mitigate ongoing pathology in a diseased brain.
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| Animal Protocol |
In vivo animal studies for NQTrp have been conducted in Drosophila melanogaster models expressing human Aβ1-42 in the nervous system. In these experiments, transgenic flies expressing Aβ1-42 are fed or exposed to NQTrp, and their lifespan is monitored and compared to untreated transgenic controls. The significant extension of lifespan observed with NQTrp treatment demonstrates that the compound can effectively cross the blood-brain barrier in this model system and exert its anti-amyloidogenic effects in vivo. Additional studies have been performed in mouse models of Alzheimer's disease, such as transgenic mice expressing mutant amyloid precursor protein (APP) and presenilin-1 (PS1). In these mammalian models, NQTrp is typically administered via intraperitoneal injection or oral gavage, and outcomes are assessed through a combination of behavioral tests (e.g., Morris water maze, novel object recognition), biochemical analyses of brain tissue (e.g., Aβ levels, plaque burden, tau pathology), and histological examinations. The complete phenotypic recovery demonstrated in these models provides strong evidence for the therapeutic potential of NQTrp in Alzheimer's disease.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of NQTrp indicate that it has a molecular weight of 360.36 and a molecular formula of C21H16N2O4. The compound is soluble in DMSO at a concentration of 20 mg/mL, facilitating its use in in vitro assays and formulation for in vivo administration. For storage, the powder should be kept at 2-8°C, and stock solutions should be stored under appropriate conditions to maintain stability. The compound's physicochemical properties, including its LogP and polar surface area, suggest that it has reasonable drug-like characteristics, although its ability to cross the blood-brain barrier would be a critical consideration for its development as a central nervous system therapeutic. In Drosophila models, the compound demonstrates sufficient bioavailability to exert its effects, and in mammalian models, its pharmacokinetic profile would need to be optimized for clinical translation, potentially through formulation strategies to enhance oral bioavailability and brain penetration.
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| Toxicity/Toxicokinetics |
Toxicological information for NQTrp is derived from preclinical studies in cellular and animal models. The compound has demonstrated no toxic effect toward retinal cell culture (ARPE-19 cells), suggesting a favorable safety profile in these cells. In neuronal cell lines, NQTrp increases cell viability in the presence of Aβ oligomers, indicating that it not only prevents Aβ-induced toxicity but is also non-toxic to the cells themselves. In Drosophila models, the compound is well-tolerated at doses that produce significant lifespan extension, suggesting a favorable therapeutic index. However, comprehensive toxicological profiling, including acute and repeated-dose toxicity studies in mammalian species, genotoxicity assessments, and cardiovascular safety evaluations, would be required to advance the compound toward clinical development. The compound's classification as a potential therapeutic for a chronic neurodegenerative disease necessitates long-term toxicology studies to assess any cumulative or delayed adverse effects. The safety profile of NQTrp appears promising based on preliminary data, but thorough evaluation is essential for clinical translation.
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| References | |
| Additional Infomation |
NQTrp is a research compound developed for the study and potential treatment of Alzheimer's disease and other proteinopathies. It is also known as 1,4-Naphthoquinon-2-yl-L-tryptophan. The compound's mechanism of action involves the inhibition of both amyloid-β and tau aggregation, making it a dual-target anti-amyloidogenic agent. NQTrp has demonstrated complete inhibition of Aβ oligomerization and fibrillization, reduction of Aβ-induced cytotoxicity, and significant extension of lifespan in Drosophila models expressing human Aβ1-42. Complete phenotypic recovery of an Alzheimer's disease model has been demonstrated using this aggregation inhibitor. The compound is not approved for clinical use and is available from research chemical suppliers for preclinical studies. Its broad-spectrum anti-amyloidogenic activity makes it a valuable tool for studying the mechanisms of protein aggregation and for developing therapeutic strategies for neurodegenerative diseases characterized by protein misfolding.
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| Molecular Formula |
C21H16N2O4
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| Molecular Weight |
360.36
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| Exact Mass |
360.111
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| CAS # |
185351-19-3
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| PubChem CID |
56605052
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| Appearance |
Brown to wine solid powder
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| LogP |
3.107
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
659
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1=CC=C2C(=C1)C(=O)C=C(C2=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)O
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| InChi Key |
DZZUYZXINNHEGM-SFHVURJKSA-N
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| InChi Code |
InChI=1S/C21H16N2O4/c24-19-10-17(20(25)15-7-2-1-6-14(15)19)23-18(21(26)27)9-12-11-22-16-8-4-3-5-13(12)16/h1-8,10-11,18,22-23H,9H2,(H,26,27)/t18-/m0/s1
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| Chemical Name |
(2S)-2-[(1,4-dioxonaphthalen-2-yl)amino]-3-(1H-indol-3-yl)propanoic acid
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| Synonyms |
NQ Trp; NQ-Trp; NQTrp
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~346.88 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.77 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.77 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7750 mL | 13.8750 mL | 27.7500 mL | |
| 5 mM | 0.5550 mL | 2.7750 mL | 5.5500 mL | |
| 10 mM | 0.2775 mL | 1.3875 mL | 2.7750 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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