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Enisamium shows potential as an antiviral therapy for COVID-19

 


Severe acute respiratory coronavirus 2 (SARS-CoV-2) affected millions of people with coronavirus disease (COVID-19) in 2019. Despite the availability of vaccines to prevent severe illness and hospitalization, there is a lack of clear antiviral therapy to treat infections.

Study: Enisamium inhibits SARS-CoV-2 RNA synthesis. Image Credit: Andrii Vodolazhskyi / Shutterstockstudy: Enisamium inhibits SARS-CoV-2 RNA synthesis.. Image Credit: Andrii Vodolazhskyi / Shutterstock

Available antiviral strategies include remdesivir or Convalescent plasma.. Nevertheless, they can only be used in the early stages of the disease and are FDA approved only for emergency use. The development of additional strategies remains relevant and necessary.

The continued emergence of a Variant of Concern (VOC) is another major concern, as mutations can help the virus evade immune responses elicited by currently available vaccines. An important target for new drug screening is the SARS-CoV-2 RNA polymerase involved in viral replication in host cells.

One of the drugs highlighted by the World Health Organization as a potential treatment for SARS-CoV-2 is enisamium. Enisamium has been approved for use against influenza in 11 countries and has been shown to reduce viral shedding and improve recovery in influenza patients. Recent studies have shown that the compound metabolite VR17-04 inhibits the activity of influenza viral RNA polymerase.

In a study recently published in the journal Biomedicine, Researchers have studied the effects of enisamium on the growth and proliferation of Caco-2 and normal human bronchial epithelial (NHBE) cells. They further investigated the molecular dynamics (MD) simulation of VR17-04 and how it stopped viral replication.

Details of the study

Researcher used In vitro A molecular biology assay to analyze the effect of enisamium on SARS-CoV-2. They first incubated Caco-2 cells, the standard cell line for SARS-CoV-2 infection, with enisamium iodide or enisamium chloride for 6 hours in the laboratory, and then infect the treated cells with SARS-CoV-2. I was allowed to.

After 48 hours, suppression of viral infection was assessed as follows: antigen Staining of viral nucleoprotein expression and RT-qPCR of viral genome replication. Later, researchers found a significant decrease in viral nucleoprotein expression, a decrease in the ability of SARS-CoV-2 to lyse and kill host (Caco-2) cells, and an exponential function of the number of infected viral genomic copies. We observed a decrease. Cells as a function of enisamium concentration.

With MD simulation analysis In vitro The activity assay suggested that the metabolite VR17-04 reversibly binds to viral RNA and prevents the replication of genetic material by completely blocking the site of RNA transcription. Therefore, viral RNA fails to replicate and cannot spread further.

In addition, the use of a newly established minigenome assay confirmed that enisamium inhibits SARS-CoV-2 nsp12 / 7/8 activity.

The research team also investigated the mechanism by which the enisamium metabolite VR17-04 inhibits the SARS-CoV-2 nsp12 / 7/8 complex. They measured the 1HNOESY spectrum of VR17-04 in water and found that VR17-04 preferentially adopted the eclipsed conformation.

Finally, the researchers tested the hypothesis that VR17-04 may form base-pair interactions with the SARS-CoV-2 nsp12 / 7/8 active site template. They did this by docking VR17-04 to the SARS-CoV-2 nsp12 / 7/8 complex bound to template RNA and remdesivir monophosphate. The findings show that VR17-04 can be adapted to the active site in a manner similar to remdesivir monophosphate. Further MD simulations suggest that VR17-04 can bind to the template cytosine or adenine base at the active site of SARS-CoV-2 RNA polymerase.

Impact on research

This study highlighted the progress in the development of antiviral therapies against the new coronavirus. The study showed that Enisamium, previously approved for influenza in 11 countries, can inhibit SARS-CoV-2 infection and viral RNA synthesis in artificial cell lines under laboratory conditions.

Unlike remdesivir, enisamium does not need to be given intravenously, so it can be used outside the hospital. This study is important for developing antiviral therapies to treat COVID-19, rather than relying on rapid vaccines.

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