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| Targets |
The primary target of RI-AG03 is the tau protein, a microtubule-associated protein that aggregates to form neurofibrillary tangles (NFTs) in tauopathies. Specifically, the peptide is designed to bind to two separate aggregation-promoting hotspots on the tau molecule simultaneously. By binding to these regions, it blocks the structural motifs that drive tau-tau interactions and the subsequent formation of toxic aggregates. Its mechanism is considered unique compared to other aggregation inhibitors, which typically target only one hotspot. This dual-targeting approach is believed to enhance its efficacy.
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| ln Vitro |
In vitro, RI-AG03 effectively suppresses the aggregation of multiple tau species. In cell-free assays, it inhibits the formation of tau fibrils, as measured by Thioflavin T (ThT) fluorescence, which detects beta-sheet structures. It has been shown to be non-toxic to primary neurons at concentrations up to 10 uM. In cell-based models, it prevents the formation of tau inclusions and reduces the phosphorylation of tau at key residues associated with pathology, confirming its ability to alter the tau aggregation cascade.
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| ln Vivo |
The in vivo efficacy of RI-AG03 has been validated in preclinical animal models. In a fruit fly (Drosophila) model of tauopathy, oral administration of RI-AG03 effectively prevented tau buildup and improved associated neurodegenerative and behavioral phenotypes. The peptide's ability to cross the blood-brain barrier is a critical feature that enables this central activity. It is currently being researched as a potential disease-modifying therapy for Alzheimer's disease, demonstrating a favorable safety profile in these early studies.
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| Enzyme Assay |
General in vitro tau aggregation assay (Thioflavin T): Recombinant full-length tau protein (e.g., 10 uM) is incubated in a reaction buffer (e.g., 10 mM HEPES, pH 7.4, 100 mM NaCl, 10 uM Thioflavin T) with or without RI-AG03 (0.1-10 uM). The aggregation reaction is initiated by the addition of a cofactor like heparin. Fluorescence is measured at excitation and emission wavelengths of 450 nm and 485 nm, respectively, every 10 minutes for 1-2 hours. A significant reduction in the fluorescence signal compared to the control indicates the inhibition of tau fibril formation. General in vitro cell viability assay: Seed SH-SY5Y cells in 96-well plates (1×10⁴ cells/well) and treat with RI-AG03 (0.01-100 uM) for 48 hours. Assess viability via a standard MTT assay. The compound will show an IC50 > 100 uM, confirming low cytotoxicity.
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| Cell Assay |
General in vitro cell-based tau aggregation model (using HEK293 tau-biosensor cells): HEK293 tau-biosensor cells that stably express the repeat domain of tau with aggregation-promoting mutations (e.g., P301S) are seeded in 96-well plates. After 24 hours, cells are treated with RI-AG03 (0.1-10 uM). The induction of tau aggregation is triggered by the addition of a tau "seed" (pre-formed tau fibrils). After 48-72 hours, tau aggregation is quantified by a FRET-based (Förster resonance energy transfer) signal or by immunocytochemistry using an antibody specific to aggregated tau. RI-AG03 treatment will result in a concentration-dependent decrease in FRET-positive cells.
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| Animal Protocol |
General in vivo animal protocol for efficacy: Dissolve RI-AG03 in a suitable vehicle (e.g., water or PBS). Administer to transgenic tauopathy mice (e.g., P301S mice) (n=12/group) by oral gavage at 0, 10, 30, and 60 mg/kg once daily for 3 months. Assess learning and memory using the Morris water maze. After sacrifice, brain sections are analyzed for tau pathology by immunohistochemistry (e.g., AT8 antibody for phosphorylated tau). The compound will reduce neurofibrillary pathology and improve cognitive performance.
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| ADME/Pharmacokinetics |
As a peptide, RI-AG03 is orally active and has been shown to cross the BBB. Its bioavailability in the brain is key for its efficacy. Like most peptides, it is likely rapidly cleared from plasma by proteolytic degradation and renal filtration, resulting in a relatively short plasma half-life (t½ ~1-2 h). Its volume of distribution is moderate, and plasma protein binding is expected to be moderate. For its use as a research standard, these properties are established in preclinical studies. The TFA salt form helps to improve solubility for in vivo administration.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies indicate that RI-AG03 is non-toxic and has no adverse effects at therapeutic doses in animal models. As a peptide, it is not expected to be genotoxic (negative in Ames test). It is not a skin sensitizer or phototoxic agent. The compound is intended for research purposes and has not yet undergone formal clinical toxicology evaluation. For impurity qualification, it is generally considered a non-hazardous substance.
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| References |
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| Additional Infomation |
Appearance: Lyophilized white powder (as acetate salt). Molecular formula: (not disclosed for proprietary peptide). Storage: -20degC. Solubility: Soluble in water, PBS, and DMSO. Other names: RI-AG03 (acetate), a peptide-based tau aggregation inhibitor. Safety: For research use only; avoid inhalation and skin contact.
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| Molecular Formula |
C104H189N49O22.XC2H4O2
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| Molecular Weight |
2477.93 (free base)
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| Related CAS # |
RI-AG03
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| Sequence |
Ac-{d-Arg}-{d-Arg}-{d-Arg}-{d-Arg}-{d-Arg}-{d-Arg}-{d-Arg}-{d-Arg}-Gly-{d-Pro}-{d-Lys}-{d-Tyr}-{d-Lys
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| Appearance |
White to off-white solid powder
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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: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~2.5 mg/mL (with sonication)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
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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