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Purity: ≥98%
PSI-6206 (also known as GS331007 and RO-2433), a deaminated derivative of PSI-6130, is a novel, potent and selective HCV NS5B polymerase inhibitor. In a subgenomic HCV replicon assay system, PSI-6206 and 2'-C-methylcytidine were shown to be strong and specific inhibitors of HCV replication. Comparing PSI-6206 to 2'-C-methylcytidine in the HCV replicon assay, it demonstrates lower cellular toxicity and more inhibitory activity.
PSI-6206 (also known as GS-331007 and RO-2433) is the deaminated (non-cytosine) uridine metabolite of the nucleoside analog PSI-6130. It is a novel, selective inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp). PSI-6206 is also the primary circulating metabolite of the blockbuster HCV drug Sofosbuvir (Sovaldi®). As the main plasma and urinary metabolite of these prodrugs, PSI-6206 is inactive or weakly active against HCV itself but requires intracellular phosphorylation to its 5′-triphosphate form (PSI-7409/RO2433-TP) for antiviral activity. The compound has a molecular formula of C₁₀H₁₃FN₂O₅ and a molecular weight of 260.22 g/mol.| Targets |
HCV (EC90 >100 μM)
PSI-6206 targets the RNA-dependent RNA polymerase (RdRp) of RNA viruses. Specifically, its active intracellular triphosphate metabolite (PSI-7409/RO2433-TP) is a potent inhibitor of the HCV NS5B polymerase, acting as a competitive inhibitor of native RNA synthesis. The IC₅₀ values for the active triphosphate form against HCV replicase and recombinant NS5B polymerase are 1.19 μM and 0.52 μM, respectively (with a Ki of 0.141 μM). |
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| ln Vitro |
PSI-6206 itself demonstrates no direct anti-HCV activity or cytotoxicity in standard cell-based replicon or bovine viral diarrhea virus assays (EC₉₀ > 100 μM). Its antiviral activity is dependent on intracellular conversion to the 5′-triphosphate metabolite (RO2433-TP), which inhibits RNA synthesis by the native HCV replicase and recombinant NS5B polymerase. In the context of Coxsackievirus B3 (CVB3), PSI-6206 inhibits virus-induced cytopathic effect with an EC₅₀ of approximately 34.6 μM and a selectivity index (SI) greater than 10, indicating low cytotoxicity (CC₅₀ > 1000 μM). When combined with dasabuvir, PSI-6206 exhibits a strong synergistic antiviral effect against CVB3 replication.
PSI-6206 (RO 2433) is subjected to surrogate bovine viral diarrhea virus (BVDV) assays as well as a cell-based quantitative real-time RT-PCR assay to assess its anti-HCV activity. No assay shows any activity or cytotoxicity from PSI-6206[1]. PSI-6130 (PSI-6130-TP) and RO2433 (RO2433-TP) both form 5′-triphosphate (TP) that steadily increases over time, reaching steady state levels after 48 hours. Additionally, RO2433-TP prevents both the recombinant HCV polymerase NS5B and the native HCV replicase that is separated from HCV replicon cells from synthesizing RNA[2]. A strong and specific inhibitor of HCV NS5B polymerase, PSI-6206 (RO2433) is the deaminated derivative of PSI-6130[3]. |
| ln Vivo |
As the primary metabolite of Sofosbuvir, its in vivo activity is achieved through the parent drug's conversion. In clinical pharmacokinetic studies of the prodrug GS-9851 (a Sofosbuvir analog), the majority of systemic drug exposure was from the nucleoside PSI-6206 (GS-331007).
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| Enzyme Assay |
The active 5′-triphosphate metabolite (RO2433-TP) was evaluated for inhibition of RNA synthesis. The compound inhibited the RNA synthesis activity of native HCV replicase isolated from HCV replicon cells with an IC₅₀ of 1.19 μM. It also inhibited the RNA synthesis activity of recombinant HCV Con1 NS5B polymerase on a heteropolymeric RNA template derived from the 3′-end of the negative strand of the HCV genome with an IC₅₀ of 0.52 μM and a Ki value of 0.141 μM.
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| Cell Assay |
HeLa cells were cultured and treated with two-fold serial dilutions of PSI-6206 to determine cytotoxicity (CC₅₀) via MTT assay. To determine antiviral activity (EC₅₀), HeLa cells infected with Coxsackievirus B3 (CVB3) were treated with serial dilutions of the compound. After incubation, cell viability was measured to calculate the 50% effective concentration. Additionally, virus yield reduction assays were performed, and viral protein (3D) and RNA levels were measured by Western blotting and qRT-PCR, respectively.
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| Animal Protocol |
Pharmacokinetic studies were conducted in rhesus monkeys using the parent drug PSI-6130. Monkeys received an intravenous (i.v.) dose (33.3 mg/kg) or oral dose (33.3 mg/kg) of PSI-6130. Blood and cerebrospinal fluid samples were collected at various time points to analyze the concentrations of the parent drug and its deaminated metabolite, PSI-6206.
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| ADME/Pharmacokinetics |
In rhesus monkeys, PSI-6206 is the primary deaminated metabolite of PSI-6130. Following i.v. administration of PSI-6130 (33.3 mg/kg), 18.9% ± 6.6% of the dose was recovered in urine as PSI-6206. Following oral administration of PSI-6130 (33.3 mg/kg), 3.9% ± 1.0% was recovered in urine as PSI-6206. The total oral bioavailability of PSI-6130 plus PSI-6206 was 64% ± 26%. In human clinical studies of the prodrug GS-9851, the terminal elimination half-life (t₁/₂) of PSI-6206 increased with dose, reaching 25.7 hours at the 800 mg dose of GS-9851. The majority of drug recovered in urine was in the form of PSI-6206.
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| Toxicity/Toxicokinetics |
PSI-6206 is classified as a non-hazardous substance and is intended for research use only, not for human or veterinary use. In vitro, PSI-6206 shows low cytotoxicity, with an estimated CC₅₀ > 1000 μM in HeLa cells. No significant toxicity was observed in cell-based assays, and the compound is not listed as carcinogenic by NTP, IARC, OSHA, or ACGIH.
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| References |
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| Additional Infomation |
PSI-6206 is the primary circulating and urinary metabolite of the blockbuster anti-HCV drug Sofosbuvir (Sovaldi®). While inactive against HCV itself, its triphosphate form is a potent inhibitor of the HCV NS5B polymerase. The S282T mutation in the NS5B polymerase gene confers resistance to the active triphosphate form. PSI-6206 has also shown potential for repurposing in combination therapy against Coxsackievirus B3 (CVB3) infections, exhibiting a strong synergistic antiviral effect when combined with dasabuvir. The compound is soluble in DMSO, water (47 mg/mL), and ethanol (22 mg/mL). Powder can be stored at -20°C for up to 3 years, and solutions can be stored at -80°C for up to 6 months.
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| Molecular Formula |
C10H13FN2O5
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|---|---|
| Molecular Weight |
260.2190
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| Exact Mass |
260.08
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| Elemental Analysis |
C, 46.16; H, 5.04; F, 7.30; N, 10.77; O, 30.74
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| CAS # |
863329-66-2
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| Related CAS # |
PSI-6206-13C,d3;1256490-42-2
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| PubChem CID |
11311503
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| Appearance |
White to off-white solid powder
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| Density |
1.6±0.1 g/cm3
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| Melting Point |
237-238℃
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| Index of Refraction |
1.596
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| LogP |
-0.77
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
18
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| Complexity |
415
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| Defined Atom Stereocenter Count |
4
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| SMILES |
C[C@]1([C@H](O)[C@@H](CO)O[C@H]1N1C=CC(=O)NC1=O)F
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| InChi Key |
ARKKGZQTGXJVKW-VPCXQMTMSA-N
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| InChi Code |
InChI=1S/C10H13FN2O5/c1-10(11)7(16)5(4-14)18-8(10)13-3-2-6(15)12-9(13)17/h2-3,5,7-8,14,16H,4H2,1H3,(H,12,15,17)/t5-,7-,8-,10-/m1/s1
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| Chemical Name |
1-[(2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidine-2,4-dione
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| Synonyms |
RO-2433; RO2433; RO 2433; PSI6206; PSI 6206; PSI-6206; GS-331007; GS 331007; GS331007
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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 |
| 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: ~52 mg/mL (~199.8 mM)
Ethanol: ~24 mg/mL (~92.2 mM) Water: ~52 mg/mL (~199.8 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.61 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 25.0 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: ≥ 2.5 mg/mL (9.61 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 25.0 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (9.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.8429 mL | 19.2145 mL | 38.4290 mL | |
| 5 mM | 0.7686 mL | 3.8429 mL | 7.6858 mL | |
| 10 mM | 0.3843 mL | 1.9215 mL | 3.8429 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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