They discover a compound effective against avian influenza viruses

Seasonal influenza viruses seriously impact public health and the economy. Per year, About one billion people worldwide are infected with the virus Millions of people require hospitalization and advanced medical care. Over 600,000 people have died from the disease during the pandemic. When zoonotic influenza viruses spread into humans, they can cause large-scale epidemics and cause greater death.Flu vaccine Existing ones provide moderate protectionbut efficacy is reduced in susceptible populations and during pandemic strains or strains incompatible with vaccine strains.

Currently, the U.S. Food and Drug Administration (FDA) Three different classes of antiviral drugs have been approved to fight influenza: amantadine (i.e., amantadine), which blocks the M2 viral channel; inhibitor of viral neuraminidase (NA) activity (i.e., oseltamivir phosphate); and baloxavir marboxil, a PA endonuclease blocker.

While initially effective when administered shortly after infection, each of these classes has a lower genetic barrier to viral resistance. For example, Overuse of Emery by Veterinarians The unique M2 S31N resistance mutation is widespread among circulating human and animal influenza A virus (IAV) strains and is no longer recommended for use in the treatment of influenza.For disease control and prevention since 2006

Resistance to treatment with neuraminidase inhibitors and baloxavir and maboxil is also rapidly emerging.

In previous research, Research finds 4′-fluorouridine (FlU)Is a broad-spectrum nucleoside analog that is effective against a variety of ribonucleic acid (RNA) viruses, including betacoronavirus, respiratory syncytial virus (RSV), and avian influenza viruses, and has been shown to wide range of activities and a wider treatment time window.

In vivo and in vitro assessment

Therefore, in a recent work, US researchers explore 4′-FlU’s therapeutic potential Assessment of pathogenesis and fitness of drug-resistant recombinants by drug resistance profiling and in vitro and in vivo.

The study involved the stepwise adaptation of recombinant CA09 virus (recCA09) to 4′-FlU by serial passage at escalating doses in six independent lineages in vitro. Progeny virus titers were determined at each passage, and whole-genome sequencing was performed on the virus population from the 4′-FlU experiment and the dimethyl sulfoxide (DMSO)-treated control population to identify the RNA-dependent RNA polymerase (RdRp ) dominant allelic mutations in. ).

Locating mutations using structural models.This process is designed to assess Development of resistance and understanding the genetic changes associated with 4′-FLU tolerance. A dose-response assay was performed against recCA09 to determine the inhibitory concentration of 4′-FIU.

To assess 4′-FlU resistance to influenza viruses, a model was used in vitro and in vivo, including cells, mice and ferrets. Additionally, computer models are used for mechanical characterization. The virus is administered intranasally.

Viral loads were monitored periodically in nasal washes (from ferrets) and respiratory tissues of mice and ferrets collected 4 or 8 days postinfection.

Dose-response evaluation of 4′-FlU against recCA09 shows inhibitory concentration 50 and 90% (EC 50 and EC 90 respectively) 0.14 and 0.24 μM.

During the in vitro adaptation of the virus to 4′-FlU, six lineages with different mutations were generated.A 2- to 25-fold increase in the EC 99 concentration of 4′-FlU was observed for different lineages, “which Moderate resistance confirmed”they explained.

Reduce viral load in tissues

On the other hand, all variants showed adaptive impairment and attenuation in cell culture and mouse models. Although the drug-resistant variant remains pathogenic in mice, Its moderate resistance to 4′-FlU can be pharmacologically overcome in vivo.

The results found that “oral administration of the lowest (2 mg/kg) or high (10 mg/kg) dose of 4′-FlU effectively overcome resistance, as shown by the survival of mice. ” The positive effect of 4′-FIU was also evident in reducing clinical symptoms and lowering viral load in tissues.

Even in the case of variants with greater resistance or residual pathogenicity, their spread is compromised and/or easily controlled by standard doses of 4′-FlU.In the ferret model, “4′-FlU-treated variants (representing four adaptive lineages) were shown to be less invasive of the lower respiratory tract, which preventing them from spreading effectively or prevent its spread to untreated sentinels. “

The authors praise the data, but they emphasize Study limitationswhich included “Uncertainty whether the observed 4′-FlU resistance exists as determined in various experimental systems” The same applies to human host“.

In summary, this study elucidates the mechanism by which influenza virus sensitivity is reduced to 4′-FIU. In mouse and ferret models, “Studies have shown that, while escape of 4′-FlU is possible, it is associated with attenuated virus and reduced transmissibility.”

Therefore, “we found that influenza-resistant populations were unable to achieve clinical significance or persist in circulation in real-world settings,” emphasizes The compound’s ongoing therapeutic potential”. The researchers say that future studies “could be conducted to explore human applications and dosage levels of 4′-FIU.”