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| 25mg |
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| Targets |
The primary target of NITD008 is the flavivirus RNA-dependent RNA polymerase (RdRp), an essential enzyme for viral replication. As an adenosine nucleoside analog, NITD008 is incorporated into the growing viral RNA chain during replication, causing chain termination and inhibiting viral RNA synthesis. The compound's 7-deaza modification at the N-7 position of the purine ring and the 2′-acetylene group on the ribose moiety contribute to its selectivity for viral polymerases over host polymerases. NITD008 inhibits Dengue Virus Type 2 (DENV-2) with an EC50 of 0.64 μM. It also shows activity against other flaviviruses, including hepatitis C virus, Zika virus, and tick-borne flaviviruses. The compound's antiviral activity against caliciviruses suggests it may target a conserved feature of viral polymerases.
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| ln Vitro |
NITD008 exhibits efficacy against various different viruses, including as the Poisson virus, West Nile virus, dengue virus (DENV), and yellow fever virus. With an EC50 value of 0.64 μM, NITD008 suppresses DENV-2 in a dose-responsive manner; treatment with 9 μM of the chemical can reduce viral titers by more than 104 times [1]. With an EC50 value of 0.11 μM, NITD008 also suppresses the luciferase reporter replicon of the hepatitis C virus (HCV, genotype 1b), a member of the genus Hepatitis C virus [1].
In vitro, NITD008 is a potent and selective flavivirus inhibitor. It inhibits Dengue Virus Type 2 (DENV-2) with an EC50 of 0.64 μM. The known EC50 of NITD008 lies between the range of 0.16–2.61 μM. NITD008 also inhibits hepatitis C virus, Zika virus, and tick-borne flaviviruses in vitro. The compound has potent antiviral activity against human and animal caliciviruses, with EC50 values of 0.94 μM, 0.91 μM, and 0.21 μM for MNV, FCV, and the Norwalk replicon, respectively. NITD008 has limited toxicity in cell-based assays. Its activity is typically measured using plaque reduction assays or focus-forming assays (FFA) in virus-infected cells. The compound's EC50 values are determined from dose-response curves. |
| ln Vivo |
NITD008 has good pharmacokinetic qualities and is orally bioavailable. When prepared using 1.5 equimolar quantities of 6 N HCl, 1 N NaOH (pH adjusted to 3.5), and 100 mM citrate buffer (pH 3.5), NITD008 showed optimum pharmacokinetic characteristics. NITD008 has a long elimination half-life (t1/2=4.99 h) following intravenous administration due to its high volume of distribution (3.71 L/kg) and low systemic clearance (31.11 mL/min/kg). NITD008 is quickly absorbed (peak plasma concentration time = 0.5 h) upon po dose, with a maximum plasma concentration of 3 μM and a 48% bioavailability. NITD008 at a dose of 1 mg/kg did not lower mortality in mice immediately following viral infection; however, therapy at a dose of 3 mg/kg offered partial protection, and treatment at a dose of ≥10 mg/kg totally prevented the virus from killing the mice. NITD008 lowers cytokine increases, controls viremia peaks, and averts death [1].
In vivo, NITD008 has demonstrated oral efficacy in animal models. As a synthetic adenosine nucleoside analog, it is orally bioavailable and has shown efficacy in flavivirus infection models. The compound's potent antiviral activity against multiple flaviviruses makes it a promising candidate for the treatment of dengue fever, Zika virus infection, and other flaviviral diseases. NITD008 has limited toxicity in vivo. While specific in vivo efficacy data are not extensively detailed in the available literature, its mechanism of action and in vitro potency suggest that it would be effective in reducing viral load and improving outcomes in flavivirus-infected animals. The compound's oral bioavailability supports convenient dosing. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for NITD008 involve polymerase inhibition assays using purified flavivirus RNA-dependent RNA polymerase (RdRp). The compound's inhibitory activity is measured by monitoring the incorporation of radiolabeled nucleotides into RNA in the presence of the enzyme and varying concentrations of NITD008. IC50 or EC50 values are determined from dose-response curves. The compound's ability to cause chain termination during RNA synthesis can be assessed using primer extension assays. Selectivity profiling against host polymerases is performed to assess the compound's specificity. These assays confirm that NITD008 directly inhibits viral polymerase activity.
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| Cell Assay |
In vitro cellular assays for NITD008 are conducted in virus-infected cell lines, such as Vero cells or BHK-21 cells. Cells are infected with Dengue virus, Zika virus, or other flaviviruses and treated with varying concentrations of NITD008. Viral replication is assessed by measuring viral RNA levels using qRT-PCR, viral titers using plaque assays, or viral protein expression using immunofluorescence. EC50 values are determined from dose-response curves. The compound's selectivity index is calculated by comparing its antiviral activity to its cytotoxicity in uninfected cells. These assays confirm that NITD008 engages its target in a cellular context and produces the expected inhibition of viral replication.
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| Animal Protocol |
In vivo animal studies for NITD008 are conducted in mouse models of flavivirus infection. Animals are infected with Dengue virus, Zika virus, or other flaviviruses and then treated with NITD008 orally. Viral load in blood and tissues is measured using qRT-PCR or plaque assays. The compound's ability to reduce viral load, improve survival, and ameliorate disease symptoms is assessed. Pharmacokinetic studies are performed to determine the compound's oral bioavailability, half-life, and tissue distribution. The compound's limited toxicity in vivo has been noted. These studies confirm that NITD008 is effective in vivo and provide information about its therapeutic potential for flaviviral diseases.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of NITD008 indicate that it has a molecular weight of 290.27 and a molecular formula of C13H14N4O4. The compound is a synthetic adenosine nucleoside analog that is orally bioavailable. It is soluble in DMSO, facilitating its use in in vitro assays and formulation for in vivo administration. For storage, the powder should be kept under appropriate conditions to maintain stability. The compound contains an Alkyne group, which enables its use in click chemistry applications. Its purity is typically ≥98% by HPLC. The compound's molecular weight and physicochemical properties suggest that it has favorable drug-like characteristics for oral administration.
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| Toxicity/Toxicokinetics |
Toxicological information for NITD008 is derived from preclinical studies. The compound has limited toxicity in cell-based assays and in vivo models. As a nucleoside analog, potential on-target effects could include inhibition of host polymerases and mitochondrial toxicity, which are well-documented class effects of nucleoside analogs. However, NITD008's selectivity for viral polymerases over host polymerases is designed to minimize these toxicities. Comprehensive toxicology studies would be required for clinical development, including assessments of mitochondrial function, hematological parameters, and hepatic and renal function. The compound's safety profile appears promising based on preliminary data.
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| References | |
| Additional Infomation |
NITD008 is a potent and selective flavivirus inhibitor, specifically a 7-deaza-adenosine analog with a 2′-acetylene modification on the ribose moiety. It is also known as 7-Deaza-2'-C-acetylene-adenosine. The compound inhibits Dengue Virus Type 2 (DENV-2) with an EC50 of 0.64 μM. NITD008 also inhibits hepatitis C virus, Zika virus, and tick-borne flaviviruses in vitro. It has potent antiviral activity against caliciviruses. NITD008 is a click chemistry reagent containing an Alkyne group. It is not approved for clinical use and is available from research chemical suppliers for preclinical studies.
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| Molecular Formula |
C13H14N4O4
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|---|---|
| Molecular Weight |
290.275
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| Exact Mass |
290.101
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| CAS # |
1044589-82-3
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| PubChem CID |
44633776
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| Appearance |
White to gray solid powder
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| Density |
1.6±0.1 g/cm3
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| Boiling Point |
631.8±55.0 °C at 760 mmHg
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| Flash Point |
335.9±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.740
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| LogP |
1.07
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
21
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| Complexity |
455
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| Defined Atom Stereocenter Count |
4
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| SMILES |
C#C[C@]1([C@@H]([C@H](O[C@H]1N2C=CC3=C(N=CN=C32)N)CO)O)O
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| InChi Key |
NKRAIOQPSBRMOV-NRMKKVEVSA-N
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| InChi Code |
InChI=1S/C13H14N4O4/c1-2-13(20)9(19)8(5-18)21-12(13)17-4-3-7-10(14)15-6-16-11(7)17/h1,3-4,6,8-9,12,18-20H,5H2,(H2,14,15,16)/t8-,9-,12-,13-/m1/s1
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| Chemical Name |
(2R,3R,4R,5R)-2-(4-Aminopyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-(hydroxymethyl)oxolane-3,4-diol
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| Synonyms |
NITD 008NITD008 NITD-008
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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 : ≥ 50 mg/mL (~172.25 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.61 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 (8.61 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 (8.61 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 | 3.4449 mL | 17.2247 mL | 34.4495 mL | |
| 5 mM | 0.6890 mL | 3.4449 mL | 6.8899 mL | |
| 10 mM | 0.3445 mL | 1.7225 mL | 3.4449 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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