Alloferon and Zanamivir Show Effective Antiviral Activity against Influenza A Virus (H1N1) Infection In Vitro and In Vivo

Abstract

The use of vaccines is the most effective and reliable method for the prevention of viral infections. However, research on evaluation of effective therapeutic agents for use in treatment after infection is necessary. Zanamivir was administered through inhalation for treatment of pandemic influenza A/H1N1 in 2009. However, the emergence of drug-resistant strains can occur rapidly. Alloferon, an immunomodulatory drug developed as an NK cell activator, exerts antiviral effects against various viruses, particularly influenza viruses. Therefore, alloferon and zanamivir were administered in combination in an effort to improve the antiviral effect of zanamivir by reducing H1N1 resistance. First, we confirmed that administration of combined treatment would result in effective inhibition of viral proliferation in MDCK and A549 cells infected with H1N1. Production of IL-6 and MIP-1α in these cells and the activity of p38 MAPK and c-Jun that are increased by H1N1 were inhibited by combined treatment. Mice were then infected intranasally with H1N1, and examination of the antiviral efficacy of the alloferon/zanamivir combination was performed. The results showed that combined treatment after infection with H1N1 prevented weight loss, increased the survival rate, and improved lung fibrosis. Combined treatment also resulted in reduced infiltration of neutrophils and macrophages into the lungs. Combined treatment effectively inhibited the activity of p38 MAPK and c-Jun in lung tissue, which was increased by infection with H1N1. Therefore, the combination of alloferon/zanamivir effectively prevents the development of H1N1-mediated inflammation in the lungs by inhibiting the production of inflammatory mediators and migration of inflammatory cells into lung tissue.

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“…It also suppressed the production of IL-6 and MIP-1α in these cells and inhibited the activity of p38 MAPK and c-Jun, which were stimulated by H1N1 44 . Furthermore, the use of alloferon/zanamivir resulted in improved lung fibrosis, decreased neutrophil and macrophage infiltration in the lungs, increased survival rates in H1N1infected mice, and prevented weight loss (Lee et al, 2023). Since the antiviral effect of alloferon was signified by blockage of inflammatory signal and mediators, it indicates alloferon's antiinflammatory properties contributes to its anti-viral abilities.…”

“…Since the potent antiviral effect of alloferon against viruses is through NK cells, it is considered an ideal candidate for combination with other antiviral medications to enhance their effectiveness (Chernysh et al, 2002). An example is showcased by Lee et al where the combination of alloferon and zanamivir against influenza A virus (H1N1) infection in vitro and in vivo effectively prevented the development of H1N1-mediated inflammation in the lungs by inhibiting the production of inflammatory mediators and blocking the migration of inflammatory cells into lung tissue (Lee et al, 2023). The combined treatment effectively controlled viral proliferation in MDCK and A549 cells infected with H1N1.…”

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“…They also exhibit antitumor and antiviral properties. Alloferon-1 has been implicated in regulating acute and chronic inflammatory responses in various diseases, such as skin and corneal epithelial cells, rheumatoid arthritis, and asthma (Ryu et al, 2008;Zhang et al, 2014;Jo et al, 2022;Lee et al, 2023). Cantharidin, a toxic compound extracted from blister beetles such as Mylabris phalerata and M. cichorii, has demonstrated promising antitumor effects by inhibiting the proteins phosphatase 1 (PP1) and phosphatase 2A (PP2A).…”

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“…It was discovered using molecular modeling techniques that predicted the optimal structure of the drug for binding to its target enzyme, the neuraminidase protein. This led to the development of a potent and specific inhibitor of this enzyme [ 130 ]. Darunavir is an anti-HIV drug that was developed using molecular dynamics simulations to optimize its binding to the HIV protease enzyme.…”

“…It was discovered using molecular modeling techniques that predicted the optimal structure of the drug for binding to its target enzyme, the neuraminidase protein. This led to the development of a potent and specific inhibitor of this enzyme [ 130 ].…”