Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model.
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ABSTRACT:
SUBMITTER: Driouich JS
PROVIDER: S-EPMC7979801 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundFavipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV-2. First efficacy data have been recently reported in COVID-19 patients.MethodsWe here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. The infected hamsters were treated twice daily with the vehicle (the control group) or a suboptimal dose of each compound or a combination of both compounds.FindingsWhen animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Infectious virus titers in the lungs of animals treated with the combination are reduced by ∼5 log10 and infectious virus are no longer detected in the lungs of >60% of treated animals. When start of treatment was delayed with one day a reduction of titers in the lungs of 2.4 log10 was achieved. Moreover, treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals. In the combo-treated hamsters, an increased frequency of C-to-T mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination.InterpretationOur findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir/Favipiravir in the treatment of COVID-19.Fundingstated in the acknowledgment.
| S-EPMC8461366 | biostudies-literature
Project description:To address the unprecedented global public health crisis due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we designed and developed a novel antiviral nano-drug, called SNAT (Smart Nano-Enabled Antiviral Therapeutic), comprised of taxoid (Tx)-decorated amino (NH2)-functionalized near-atomic size positively charged silver nanoparticles (Tx-[NH2-AgNPs]) that are stable for over 3 years. Using a hamster model, we tested the preclinical efficacy of inhaled SNAT on the body weight, virus titer, and histopathology of lungs in SARS-CoV-2-infected hamsters, including biocompatibility in human lung epithelium and dermal fibroblasts using lactase dehydrogenase (LDH) and malondialdehyde (MDA) assays. Our results showed SNAT could effectively reverse the body weight loss, reduce the virus load in oral swabs, and improve lung health in hamsters. Furthermore, LDH assay showed SNAT is noncytotoxic, and MDA assay demonstrated SNAT to be an antioxidant, potentially quenching lipid peroxidation, in both the human cells. Overall, these promising pilot preclinical findings suggest SNAT as a novel, safer antiviral drug lead against SARS-CoV-2 infection and may find applications as a platform technology against other respiratory viruses of epidemic and pandemic potential.
| S-EPMC9017740 | biostudies-literature
Project description:Nipah and Hendra viruses are recently emerged bat-borne paramyxoviruses (genus Henipavirus) causing severe encephalitis and respiratory disease in humans with fatality rates ranging from 40-75%. Despite the severe pathogenicity of these viruses and their pandemic potential, no therapeutics or vaccines are currently approved for use in humans. Favipiravir (T-705) is a purine analogue antiviral approved for use in Japan against emerging influenza strains; and several phase 2 and 3 clinical trials are ongoing in the United States and Europe. Favipiravir has demonstrated efficacy against a broad spectrum of RNA viruses, including members of the Paramyxoviridae, Filoviridae, Arenaviridae families, and the Bunyavirales order. We now demonstrate that favipiravir has potent antiviral activity against henipaviruses. In vitro, favipiravir inhibited Nipah and Hendra virus replication and transcription at micromolar concentrations. In the Syrian hamster model, either twice daily oral or once daily subcutaneous administration of favipiravir for 14 days fully protected animals challenged with a lethal dose of Nipah virus. This first successful treatment of henipavirus infection in vivo with a small molecule drug suggests that favipiravir should be further evaluated as an antiviral treatment option for henipavirus infections.
| S-EPMC5954062 | biostudies-literature
Project description:Hantavirus pulmonary syndrome (HPS) is caused by infection with several Sigmodontinae- and Neotominae-borne hantaviruses and has a case fatality rate of 30 to 50%. Humans often become infected by inhalation of materials contaminated with virus-laden rodent urine or saliva, although human-to-human transmission has also been documented for Andes virus (ANDV). The ability to transmit via aerosolization, coupled with the high mortality rates and lack of therapeutic options, makes the development of medical countermeasures against HPS imperative. In the present study, we evaluated the efficacy of the broad-spectrum antiviral agent favipiravir (T-705) against Sin Nombre virus (SNV) and ANDV, the predominant causes of HPS in North and South America, respectively. In vitro, T-705 potently inhibited SNV and ANDV, as evidenced by decreased detection of viral RNA and reduced infectious titers. For both viruses, the 90% effective concentration was estimated at ?5 ?g/ml (?31.8 ?M). In the lethal ANDV hamster model, daily administration of oral T-705 at 50 or 100 mg/kg of body weight diminished the detection of viral RNA and antigen in tissue specimens and significantly improved survival rates. Oral T-705 therapy remained protective against HPS when treatment was initiated prior to the onset of viremia. No disease model for SNV exists; however, using a hamster-adapted SNV, we found that daily administration of oral T-705 significantly reduced the detection of SNV RNA and antigen in tissue specimens, suggesting that the compound would also be effective against HPS in North America. Combined, these results suggest that T-705 treatment is beneficial for postexposure prophylaxis against HPS-causing viruses and should be considered for probable exposures.
| S-EPMC3811478 | biostudies-other
Project description:The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics.
| S-SCDT-10_1038-S44319-024-00189-4 | biostudies-other
Project description:BACKGROUND:Despite repeated outbreaks, in particular the devastating 2014-2016 epidemic, there is no effective treatment validated for patients with Ebola virus disease (EVD). Among the drug candidates is the broad-spectrum polymerase inhibitor favipiravir, which showed a good tolerance profile in patients with EVD (JIKI trial) but did not demonstrate a strong antiviral efficacy. In order to gain new insights into the antiviral efficacy of favipiravir and improve preparedness and public health management of future outbreaks, we assess the efficacy achieved by ascending doses of favipiravir in Ebola-virus-infected nonhuman primates (NHPs). METHODS AND FINDINGS:A total of 26 animals (Macaca fascicularis) were challenged intramuscularly at day 0 with 1,000 focus-forming units of Ebola virus Gabon 2001 strain and followed for 21 days (study termination). This included 13 animals left untreated and 13 treated with doses of 100, 150, and 180 mg/kg (N = 3, 5, and 5, respectively) favipiravir administered intravenously twice a day for 14 days, starting 2 days before infection. All animals left untreated or treated with 100 mg/kg died within 10 days post-infection, while animals receiving 150 and 180 mg/kg had extended survival (P < 0.001 and 0.001, respectively, compared to untreated animals), leading to a survival rate of 40% (2/5) and 60% (3/5), respectively, at day 21. Favipiravir inhibited viral replication (molecular and infectious viral loads) in a drug-concentration-dependent manner (P values < 0.001), and genomic deep sequencing analyses showed an increase in virus mutagenesis over time. These results allowed us to identify that plasma trough favipiravir concentrations greater than 70-80 ?g/ml were associated with reduced viral loads, lower virus infectivity, and extended survival. These levels are higher than those found in the JIKI trial, where patients had median trough drug concentrations equal to 46 and 26 ?g/ml at day 2 and day 4 post-treatment, respectively, and suggest that the dosing regimen in the JIKI trial was suboptimal. The environment of a biosafety level 4 laboratory introduces a number of limitations, in particular the difficulty of conducting blind studies and performing detailed pharmacological assessments. Further, the extrapolation of the results to patients with EVD is limited by the fact that the model is fully lethal and that treatment initiation in patients with EVD is most often initiated several days after infection, when symptoms and high levels of viral replication are already present. CONCLUSIONS:Our results suggest that favipiravir may be an effective antiviral drug against Ebola virus that relies on RNA chain termination and possibly error catastrophe. These results, together with previous data collected on tolerance and pharmacokinetics in both NHPs and humans, support a potential role for high doses of favipiravir for future human interventions.
| S-EPMC5870946 | biostudies-literature
Project description: Not available
| S-EPMC8929374 | biostudies-literature
Project description:SARS-CoV-2 causes devastating impact on the human population and has become a major public health concern. The frequent emergence of SARS-CoV-2 variants of concern urges the development of safe and efficacious vaccine against SARS-CoV-2 variants. We developed a candidate vaccine Baiya SARS-CoV-2 Vax 1, based on SARS-CoV-2 receptor-binding domain (RBD) by fusing with the Fc region of human IgG. The RBD-Fc fusion was produced in Nicotiana benthamiana. Previously, we reported that this plant-produced vaccine is effective in inducing immune response in both mice and non-human primates. Here, the efficacy of our vaccine candidate was tested in Syrian hamster challenge model. Hamsters immunized with two intramuscular doses of Baiya SARS-CoV-2 Vax 1 induced neutralizing antibodies against SARS-CoV-2 and protected from SARS-CoV-2 challenge with reduced viral load in the lungs. These preliminary results demonstrate the ability of plant-produced subunit vaccine Baiya SARS-CoV-2 Vax 1 to provide protection against SARS-CoV-2 infection in hamsters.
| S-EPMC9744481 | biostudies-literature
Project description:There are a number of uncertainties regarding plasma protein binding and blood distribution of the active drugs favipiravir (FAVI), molnupiravir (MOLNU) and imatinib (IMA), which were recently proposed as therapeutics for the treatment of COVID-19 disease. Therefore, proton dissociation processes, solubility, lipophilicity, and serum protein binding of these three substances were investigated in detail. The drugs display various degrees of lipophilicity at gastric (pH 2.0) and blood pH (pH 7.4). The determined pKa values explain well the changes in lipophilic character of the respective compounds. The serum protein binding was studied by membrane ultrafiltration, frontal analysis capillary electrophoresis, steady-state fluorometry, and fluorescence anisotropy techniques. The studies revealed that the ester bond in MOLNU is hydrolyzed by protein constituents of blood serum. Molnupiravir and its hydrolyzed form do not bind considerably to blood proteins. Likewise, FAVI does not bind to human serum albumin (HSA) and α1-acid glycoprotein (AGP) and shows relatively weak binding to the protein fraction of whole blood serum. Imatinib binds to AGP with high affinity (logK' = 5.8-6.0), while its binding to HSA is much weaker (logK' ≤ 4.0). The computed constants were used to model the distribution of IMA in blood plasma under physiological and 'acute-phase' conditions as well.
| S-EPMC9917862 | biostudies-literature
Project description:The emergence of the SARS-CoV-2 Delta variant (B.1.617.2) raises concerns about potential reduced sensitivity of the virus to antibody neutralization and subsequent vaccine breakthrough infections. Here, we use a live virus neutralization assay with sera from Pfizer- and Moderna-vaccinated individuals to examine neutralizing antibody titers against SARS-CoV-2 and observe a 3.9- and 2.7-fold reduction, respectively, in neutralizing antibody titers against the Delta variant compared with an early isolate bearing only a D614G substitution in its spike protein. We observe similar reduced sensitivity with sera from hamsters that were previously infected with an early isolate of SARS-CoV-2. Despite this reduction in neutralizing antibody titers against the Delta variant, hamsters previously infected (up to 15 months earlier) with an early isolate are protected from infection with the Delta variant, suggesting that the immune response to the first infection is sufficient to provide protection against subsequent infection with the Delta variant.
| S-EPMC8801307 | biostudies-literature