LAUSR

&NA; Although vaccines confer protection against influenza A viruses, antiviral treatment becomes the first line of defense during pandemics because there is insufficient time to produce vaccines. Current antiviral drugs are susceptible to drug resistance, and developing new antivirals is essential. We studied host defense peptides from the skin of the South Indian frog and demonstrated that one of these, which we named “urumin,” is virucidal for H1 hemagglutinin‐bearing human influenza A viruses. This peptide specifically targeted the conserved stalk region of H1 hemagglutinin and was effective against drug‐resistant H1 influenza viruses. Using electron microscopy, we showed that this peptide physically destroyed influenza virions. It also protected naive mice from lethal influenza infection. Urumin represents a unique class of anti‐influenza virucide that specifically targets the hemagglutinin stalk region, similar to targeting of antibodies induced by universal influenza vaccines. Urumin therefore has the potential to contribute to first‐line anti‐viral treatments during influenza outbreaks. HighlightsThe frog skin peptide urumin is virucidal for H1 HA‐bearing human influenza A virusesUrumin specifically targets the conserved stalk of H1 hemagglutininUrumin is effective at neutralizing drug‐resistant H1 influenza virusesUrumin protects naive mice from lethal influenza infection in vivo &NA; Antiviral treatment is the first line of defense during influenza A pandemics. Holthausen et al. identify a host defense peptide (urumin) from frogs that is virucidal for H1 hemagglutinin (HA)‐bearing human influenza A viruses. Urumin targets the conserved stalk region of hemagglutinin and protects naive mice from lethal influenza infection.