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| Targets |
EC50: 5-28 nM (HCV)[1] EC90: 0.47 μM (SARS-CoV-2)[2]
Bemnifosbuvir targets the RNA-dependent RNA polymerase (RdRp) of single-stranded RNA viruses, including HCV NS5B polymerase and the SARS-CoV-2 RdRp. The active triphosphate metabolite, AT-9010, acts as a chain terminator, incorporating into the growing viral RNA strand and causing premature termination of RNA synthesis. Additionally, the combination of bemnifosbuvir with ruzasvir targets both the HCV NS5B and NS5A proteins, which are essential for HCV replication. |
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| ln Vitro |
Bemnifosbuvir exhibits pan-genotypic antiviral activities: it inhibits the replication of HCV genotype 1a (HCV GT1a), HCV GT1b, HCV GT2a, HCV GT3a, HCV GT4a, and HCV GT5a with EC50 values of 12.8 nM, 12.5 nM, 9.2 nM, 10.3 nM, 14.7 nM, and 28.5 nM, respectively[1]. The dose of Bemnifosbuvir needed to prevent SARS-CoV-2 replication via EC90 in normal human airway epithelial cells is 0.47 μM, which is comparable to the concentration of EC90 needed to prevent HCoV-229E, HCoV-OC43, and SARS-CoV in Huh-7 cells[2].
Bemnifosbuvir exhibits potent, pan-genotypic antiviral activity against HCV in vitro. The combination of bemnifosbuvir and ruzasvir has demonstrated synergistic activity against HCV in vitro. For SARS-CoV-2, AT-511 has shown high effectiveness in controlling infection in vitro, with an EC90 value of 0.47 μM. Studies have also shown additive antiviral effects when combined with nirmatrelvir. The active triphosphate metabolite (AT-9010) is a potent inhibitor of the viral RdRp, with selectivity for viral over host polymerases, which contributes to its favorable safety profile. |
| ln Vivo |
Bemnifosbuvir preferentially delivers high amounts of AT-9010 in the liver in vivo when given orally to rats (500 mg/kg) and monkeys (30 mg/kg, 100 mg/kg, or 300 mg/kg)[1].
In animal models, bemnifosbuvir has demonstrated oral antiviral activity, with efficacy observed at doses of 150–250 mg/kg administered twice daily for 3 days. The compound has been evaluated in numerous clinical trials for both HCV and COVID-19. In HCV, a Phase 2 clinical trial is ongoing, evaluating bemnifosbuvir in combination with ruzasvir in treatment-naïve HCV-infected patients, with or without cirrhosis. In COVID-19, the SUNRISE-3 global Phase 3 trial evaluated bemnifosbuvir (550 mg twice daily for 5 days) in high-risk, non-hospitalized patients with mild to moderate COVID-19. The primary endpoint was all-cause hospitalization or death through Day 29. Although the trial did not meet its primary endpoint of symptom alleviation, it did show a 71% relative reduction in hospitalization risk. The results were inconsistent across different stages, with some early clinical trials showing good results that were not replicated in later stages. |
| Enzyme Assay |
Biochemical assays can be performed to measure the inhibitory activity of the active triphosphate metabolite AT-9010 against viral RNA-dependent RNA polymerase (RdRp). In a typical polymerase assay, purified recombinant RdRp enzyme (derived from HCV NS5B or SARS-CoV-2) is incubated with a synthetic RNA template-primer, nucleotide substrates (including radiolabeled or fluorescently labeled nucleotides), and varying concentrations of AT-9010. The incorporation of nucleotides into the growing RNA chain is measured, and the half-maximal inhibitory concentration (IC50) is calculated from dose-response curves. The chain-terminating mechanism of action can be confirmed by sequencing the terminated RNA products. In addition, binding studies using isothermal titration calorimetry (ITC) or surface plasmon resonance (SPR) can be employed to determine the binding affinity of AT-9010 to the polymerase active site.
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| Cell Assay |
Antiviral activity of bemnifosbuvir is assessed in cell culture models infected with HCV or SARS-CoV-2. For HCV, human hepatoma cell lines (such as Huh-7) harboring subgenomic replicons or infectious virus are treated with varying concentrations of AT-511 (the parent compound or the active metabolite). For SARS-CoV-2, Vero E6 cells or human airway epithelial cells are infected with the virus and treated with the compound. Following treatment, viral replication is quantified by measuring viral RNA levels using quantitative reverse transcription PCR (qRT-PCR), or by assessing viral titers using plaque assays or TCID50 (median tissue culture infectious dose) assays. Cytotoxicity is simultaneously assessed in uninfected cells using MTT or CellTiter-Glo assays to determine the selectivity index (SI = CC50/EC50). The combination index (CI) method is used to evaluate synergistic effects when bemnifosbuvir is combined with other antivirals such as nirmatrelvir or ruzasvir.
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| Animal Protocol |
Bemnifosbuvir has been evaluated in various preclinical animal models and clinical trials. In the SUNRISE-3 Phase 3 clinical trial for COVID-19, patients were randomized 1:1 to receive bemnifosbuvir 550 mg twice daily plus locally available standard of care (SOC) or placebo twice daily plus SOC for five days. The trial enrolled high-risk patients, including those ≥70 years old, ≥55 years old with one or more risk factors, ≥50 years old with two or more risk factors, and immunocompromised patients. The supportive care monotherapy population (approximately 2,200 patients) was assessed for the primary endpoint of all-cause hospitalization or death through Day 29. Secondary endpoints included COVID-19-related hospitalization or death, COVID-19 complications, medically attended visits, symptom rebound/relapse, and viral load rebound. For HCV, a Phase 2 trial is ongoing in treatment-naïve patients without cirrhosis or with compensated cirrhosis.
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| ADME/Pharmacokinetics |
Bemnifosbuvir is an orally bioavailable prodrug that is metabolized in several steps to the active nucleotide triphosphate AT-9010. The double prodrug strategy is designed to maximize formation of the active metabolite in target tissues while minimizing systemic exposure to the parent compound. In clinical trials, bemnifosbuvir has been administered at doses of 550 mg twice daily. The compound is rapidly absorbed after oral administration, with peak plasma concentrations achieved within a few hours. The prodrug is efficiently converted to the active triphosphate in cells, which has a prolonged intracellular half-life, allowing for once- or twice-daily dosing. The pharmacokinetic profile supports its use as an oral antiviral with good bioavailability and tissue distribution. No detailed data on Cmax, AUC, or elimination half-life has been publicly disclosed in the available literature.
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| Toxicity/Toxicokinetics |
Bemnifosbuvir has demonstrated a favorable safety profile in clinical trials. The compound was well tolerated, with no discontinuations, serious adverse events, or clinically significant changes in vital signs or electrocardiograms (ECGs) reported in early studies. In the SUNRISE-3 Phase 3 trial, the compound did not show significant safety concerns. However, a Phase III study ended early as it failed to meet its primary endpoint of symptom alleviation. The safety profile of bemnifosbuvir is consistent with that of other nucleoside analogs, with no unexpected toxicities identified. Long-term toxicity data from animal studies has not been extensively published, but the compound is generally considered to have a manageable safety profile based on clinical experience.
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| References |
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| Additional Infomation |
Benifobvir is a highly bioavailable, direct-acting antiviral purine nucleotide prodrug with potential antiviral activity against various RNA viruses. After oral administration, benifobuvir, as a prodrug, is metabolized into its active form. This active form inhibits the activity of viral RNA-dependent RNA polymerase, thereby terminating viral RNA transcription, reducing viral RNA production, and inhibiting viral RNA replication.
Mechanism of Action AT-527 is a guanosine nucleotide analog prodrug with the potential to effectively inhibit SARS-CoV-2 replication in vitro. It also inhibits NS5B polymerase in hepatitis C virus. Currently, this drug is being investigated for the treatment of COVID-19 and has previously been studied for the treatment of hepatitis C virus infection. Bemnifosbuvir (AT-527, RO7496998) is a novel, orally administered guanosine nucleotide analog polymerase inhibitor discovered by Atea Pharmaceuticals and licensed to Roche. The compound was originally developed for HCV and later repurposed for COVID-19, receiving FDA Fast Track designation for the latter indication. The mechanism of action involves inhibition of viral RNA-dependent RNA polymerase (RdRp) by the active triphosphate metabolite AT-9010, which acts as a chain terminator. For HCV, the drug is being developed in combination with ruzasvir, an NS5A inhibitor licensed from Merck, targeting both NS5B and NS5A. Despite the mixed results in COVID-19 trials, bemnifosbuvir remains a significant example of a nucleotide analog antiviral with broad-spectrum potential against single-stranded RNA viruses. |
| Molecular Formula |
C24H33FN7O7P
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|---|---|
| Molecular Weight |
581.533689260483
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| Exact Mass |
581.216
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| CAS # |
1998705-64-8
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| Related CAS # |
Bemnifosbuvir hemisulfate;2241337-84-6;HCV-IN-31;1998705-62-6
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| PubChem CID |
122527275
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
1.7
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
40
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| Complexity |
919
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| Defined Atom Stereocenter Count |
6
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| SMILES |
P(N[C@H](C(=O)OC(C)C)C)(=O)(OC1C=CC=CC=1)OC[C@@H]1[C@H]([C@](C)(C(N2C=NC3C(NC)=NC(N)=NC2=3)O1)F)O
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| InChi Key |
OISLSHLAXHALQZ-LZEIJKKFSA-N
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| InChi Code |
InChI=1S/C24H33FN7O7P/c1-13(2)37-21(34)14(3)31-40(35,39-15-9-7-6-8-10-15)36-11-16-18(33)24(4,25)22(38-16)32-12-28-17-19(27-5)29-23(26)30-20(17)32/h6-10,12-14,16,18,22,33H,11H2,1-5H3,(H,31,35)(H3,26,27,29,30)/t14-,16+,18+,22+,24+,40-/m0/s1
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| Chemical Name |
propan-2-yl (2S)-2-[[[(2R,3R,4R,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
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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 : 200 mg/mL (343.92 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.30 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 (4.30 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 (4.30 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 | 1.7196 mL | 8.5980 mL | 17.1960 mL | |
| 5 mM | 0.3439 mL | 1.7196 mL | 3.4392 mL | |
| 10 mM | 0.1720 mL | 0.8598 mL | 1.7196 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.
A Phase 2 Study Assessing the Safety and Efficacy of AT-527 in Combination with Daclatasvir in Subjects with Chronic HCV Infection
CTID: null
Phase: Phase 2 Status: Completed
Date: 2019-05-20
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