A novel entry inhibitor targeting the stalk domain of the hemagglutinin of H1N1.

Influenza is a global health issue. Vaccines can protect humans from infection from influenza virus. When no suitable vaccine is available, anti-influenza drugs are the first treatment choice. Emergence of drug resistance necessitates development of novel anti-influenza virus drugs. We investigated a novel macrocyclic compound H1N1-17 using in vitro assays. Through evaluation of its antiviral effect against H1N1 and H3N2 viruses, compound H1N1-17 showed selective inhibition of H1N1 virus strains. Invasion of pseudo-H1N1 was blocked by H1N1-17 in the entry inhibition assay. Membrane fusion of H1N1 and the endosome mediated by the stalk domain of hemagglutinin was inhibited by H1N1-17. In the induction of a drug-resistant mutations assay, the resistant sites of H1N1 to H1N1-17 were located in the F subdomain of hemagglutinin, which is crucial for membrane fusion. Intraperitoneal administration of compound H1N1-17 protected mice challenged with lethal H1N1 from death and weight loss, and effectively alleviated lung injury caused by viral infection. Additionally, compound H1N1-17 exhibited synergistic anti-influenza activity with oseltamivir acid, which was of significance for combination therapy.