An Influenza Virus Entry Inhibitor Targets Class II PI3 Kinase and Synergizes with Oseltamivir

Area of Science:

• Virology
• Drug Discovery
• Molecular Biology

Background:

• Current influenza antivirals (neuraminidase and endonuclease inhibitors) face resistance issues.
• Widespread resistance to oseltamivir in H1N1 viruses necessitates novel antiviral strategies.
• Limited antiviral targets and emerging resistance highlight the need for agents with a higher barrier to resistance.

Purpose of the Study:

• To identify novel influenza antivirals with a higher barrier to resistance.
• To investigate the antiviral mechanism of a newly identified compound, M85.
• To evaluate M85 as a potential component of combination therapy for influenza.

Main Methods:

• Screening for host-targeting antivirals.
• Characterization of M85's mechanism of action, including target identification (EGFR, PIK3C2β).
• Assessment of M85's antiviral activity against a broad spectrum of viruses in vitro and in vivo (mouse model).
• Evaluation of synergistic effects of M85 in combination with oseltamivir.

Main Results:

• M85 identified as a novel antiviral targeting host kinases EGFR and PIK3C2β.
• M85 effectively blocks influenza virus endocytosis and exhibits broad-spectrum antiviral activity with low cytotoxicity.
• In vitro studies showed strong synergism between M85 and oseltamivir.
• Combination therapy with M85 and oseltamivir provided superior protection against lethal influenza challenge in mice compared to oseltamivir alone.

Conclusions:

• M85 represents a promising new influenza antiviral candidate with a high barrier to resistance.
• PIK3C2β is identified as a novel host factor essential for influenza virus entry.
• M85 holds potential for development into effective combination therapies for influenza treatment.