The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro.
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ABSTRACT:
SUBMITTER: Wang X
PROVIDER: S-EPMC7195821 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ?16 Å from the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter- and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. This unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus.
| S-EPMC5240704 | biostudies-literature
Project description:AIM: To investigate the effects of arbidol hydrochloride (ARB), a widely used antiviral agent, on the inflammation induced by influenza virus. METHODS: MDCK cells were infected with seasonal influenza A/FM/1/47 (H1N1) or pandemic influenza A/Hubei/71/2009 (H1N1). In vitro cytotoxicity and antiviral activity of ARB was determined using MTT assay. BALB/c mice were infected with A/FM/1/47 (H1N1). Four hours later the mice were administered ARB (45, 90, and 180 mg·kg(-1)·d(-1)) or the neuraminidase inhibitor oseltamivir (22.5 mg·kg(-1)·d(-1)) via oral gavage once a day for 5 d. Body-weight, median survival time, viral titer, and lung index of the mice were measured. The levels of inflammatory cytokines were examined using real-time RT-PCR and ELISA. RESULTS: Both H1N1 stains were equally sensitive to ARB as tested in vitro. In the infected mice, ARB (90 and 180 mg·kg(-1)·d(-1)) significantly decreased the mortality, alleviated virus-induced lung lesions and viral titers. Furthermore, ARB suppressed the levels of IL-1β, IL-6, IL-12, and TNF-α, and elevated the level of IL-10 in the bronchoalveolar lavage fluids and lung tissues. However, ARB did not significantly affect the levels of IFN-α and IFN-γ, but reduced the level of IFN-β1 in lung tissues at 5 dpi. In peritoneal macrophages challenged with A/FM/1/47 (H1N1) or poly I:C, ARB (20 μmol/L) suppressed the levels of IL-1β, IL-6, IL-12, and TNF-α, and elevated the level of IL-10. Oseltamivir produced comparable alleviation of virus-induced lung lesions with more reduction in the viral titers, but less effective modulation of the inflammatory cytokines. CONCLUSION: ARB efficiently inhibits both H1N1 stains and diminishes both viral replication and acute inflammation through modulating the expression of inflammatory cytokines.
| S-EPMC4003028 | biostudies-other
Project description:Understanding mechanisms of resistance to antiviral inhibitors can reveal nuanced features of targeted viral mechanisms and, in turn, lead to improved strategies for inhibitor design. Arbidol is a broad-spectrum antiviral that binds to and prevents the fusion-associated conformational changes in the trimeric influenza A virus (IAV) hemagglutinin (HA). The rate-limiting step during the HA-mediated membrane fusion is the release of the hydrophobic fusion peptides from a conserved pocket on HA. Here, we investigated how destabilizing or stabilizing mutations in or near the fusion peptide affect viral sensitivity to Arbidol. The degree of sensitivity was proportional to the extent of fusion-peptide stability on the prefusion HA: stabilized mutants were more sensitive, and destabilized ones were resistant to Arbidol. Single-virion membrane fusion experiments for representative wild-type (WT) and mutant viruses demonstrated that resistance is a direct consequence of fusion-peptide destabilization not requiring reduced Arbidol binding to HA. Our results support the model whereby the probability of individual HAs extending to engage the target membrane is determined by the composite of two critical forces: a "tug" on the fusion peptide by HA rearrangements near the Arbidol binding site and the key interactions stabilizing the fusion peptide in the prefusion pocket. Arbidol increases and destabilizing mutations decrease the free-energy cost for fusion-peptide release, accounting for the observed resistance. Our findings have broad implications for fusion inhibitor design, viral mechanisms of resistance, and our basic understanding of HA-mediated membrane fusion.
| S-EPMC9810120 | biostudies-literature
Project description:Antiviral drugs are important in preventing and controlling influenza, particularly when vaccines are ineffective or unavailable. A single class of antiviral drugs, the neuraminidase inhibitors (NAIs), is recommended for treating influenza. The limited therapeutic options and the potential risk of antiviral resistance are driving the search for additional small-molecule inhibitors that act on influenza virus proteins. The acid polymerase (PA) of influenza viruses is a promising target for new antivirals because of its essential role in initiating virus transcription. Here, we characterized a novel compound, RO-7, identified as a putative PA endonuclease inhibitor. RO-7 was effective when added before the cessation of genome replication, reduced polymerase activity in cell-free systems, and decreased relative amounts of viral mRNA and genomic RNA during influenza virus infection. RO-7 specifically inhibited the ability of the PA endonuclease domain to cleave a nucleic acid substrate. RO-7 also inhibited influenza A viruses (seasonal and 2009 pandemic H1N1 and seasonal H3N2) and B viruses (Yamagata and Victoria lineages), zoonotic viruses (H5N1, H7N9, and H9N2), and NAI-resistant variants in plaque reduction, yield reduction, and cell viability assays in Madin-Darby canine kidney (MDCK) cells with nanomolar to submicromolar 50% effective concentrations (EC50s), low toxicity, and favorable selective indices. RO-7 also inhibited influenza virus replication in primary normal human bronchial epithelial cells. Overall, RO-7 exhibits broad-spectrum activity against influenza A and B viruses in multiple in vitro assays, supporting its further characterization and development as a potential antiviral agent for treating influenza.
| S-EPMC4997863 | biostudies-other
Project description:There are many emerging and re-emerging globally prevalent viruses for which there are no licensed vaccines or antiviral medicines. Arbidol (ARB, umifenovir), used clinically for decades in several countries as an anti-influenza virus drug, inhibits many other viruses. In the current study, we show that ARB inhibits six different isolates of Zika virus (ZIKV), including African and Asian lineage viruses in multiple cell lines and primary human vaginal and cervical epithelial cells. ARB protects against ZIKV-induced cytopathic effects. Time of addition studies indicate that ARB is most effective at suppressing ZIKV when added to cells prior to infection. Moreover, ARB inhibits pseudoviruses expressing the ZIKV Envelope glycoprotein. Thus, ARB, a broadly acting anti-viral agent with a well-established safety profile, inhibits ZIKV, likely by blocking viral entry.
| S-EPMC5997637 | biostudies-literature
Project description:Seasonal influenza and the current COVID-19 pandemic represent looming global health challenges. Efficacious and safe vaccines remain the frontline tools for mitigating both influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced diseases. This review will discuss the existing strategies for influenza vaccines and how these strategies have informed SARS-CoV-2 vaccines. It will also discuss new vaccine platforms and potential challenges for both viruses.
| S-EPMC8722349 | biostudies-literature
Project description:Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here we uncover a role of the complement system in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonizes SARS-CoV-2 particles via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently induces type-I interferon and pro-inflammatory cytokine responses via activation of dendritic cells, which are inhibited by antibodies against the complement receptors (CR) 3 and 4. Serum from COVID-19 patients, or monoclonal antibodies against SARS-CoV-2, attenuate innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking of CD32, the FcγRII antibody receptor of dendritic cells, restores complement-induced immunity. These results suggest that opsonization of SARS-CoV-2 by complement is involved in the induction of innate and adaptive immunity to SARS-CoV-2 in the acute phase of infection. Subsequent antibody responses limit inflammation and restore immune homeostasis. These findings suggest that dysregulation of the complement system and FcγRII signaling may contribute to severe COVID-19.
| S-SCDT-10_1038-S44318-024-00061-0 | biostudies-other
Project description:Coronavirus disease 2019 (COVID-19) has caused serious public health, social, and economic damage worldwide and effective drugs that prevent or cure COVID-19 are urgently needed. Approved drugs including Hydroxychloroquine, Remdesivir or Interferon were reported to inhibit the infection or propagation of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), however, their clinical efficacies have not yet been well demonstrated. To identify drugs with higher antiviral potency, we screened approved anti-parasitic/anti-protozoal drugs and identified an anti-malarial drug, Mefloquine, which showed the highest anti-SARS-CoV-2 activity among the tested compounds. Mefloquine showed higher anti-SARS-CoV-2 activity than Hydroxychloroquine in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 1.28 μM, IC90 = 2.31 μM, and IC99 = 4.39 μM in VeroE6/TMPRSS2 cells. Mefloquine inhibited viral entry after viral attachment to the target cell. Combined treatment with Mefloquine and Nelfinavir, a replication inhibitor, showed synergistic antiviral activity. Our mathematical modeling based on the drug concentration in the lung predicted that Mefloquine administration at a standard treatment dosage could decline viral dynamics in patients, reduce cumulative viral load to 7% and shorten the time until virus elimination by 6.1 days. These data cumulatively underscore Mefloquine as an anti-SARS-CoV-2 entry inhibitor.
| S-EPMC8119653 | biostudies-literature
Project description:Arbidol (ARB) is a broad-spectrum antiviral drug approved in Russia and China for the treatment of influenza. ARB was tested in patients as a drug candidate for the treatment at the early onset of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite promising clinical results and multiple ongoing trials, preclinical data are lacking and the molecular mechanism of action of ARB against SARS-CoV-2 remains unknown. Here, we demonstrate that ARB binds to the spike viral fusion glycoprotein of the SARS-CoV-2 Wuhan strain as well as its more virulent variants from the United Kingdom (strain B.1.1.7) and South Africa (strain B.1.351). We pinpoint the ARB binding site on the S protein to the S2 membrane fusion domain and use an infection assay with Moloney murine leukemia virus (MLV) pseudoviruses (PVs) pseudotyped with the S proteins of the Wuhan strain and the new variants to show that this interaction is sufficient for the viral cell entry inhibition by ARB. Finally, our experiments reveal that the ARB interaction leads to a significant destabilization and eventual lysosomal degradation of the S protein in cells. Collectively, our results identify ARB as the first clinically approved small molecule drug binder of the SARS-CoV-2 S protein and place ARB among the more promising drug candidates for COVID-19.
| S-EPMC8610013 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic is a global public health emergency, and new therapeutics are needed. This article reports the potential drug target and mechanism of action of Arbidol (umifenovir) to treat coronavirus disease 2019 (COVID-19). Molecular dynamics and structural analysis were used to show how Arbidol targets the SARS-CoV-2 spike glycoprotein and impedes its trimerization, which is key for host cell adhesion and hijacking, indicating the potential of Arbidol to treat COVID-19. It is hoped that knowledge of the potential drug target and mechanism of action of Arbidol will help in the development of new therapeutics for SARS-CoV-2.
| S-EPMC7187825 | biostudies-literature