CS-8958 is, therefore, a promising candidate antiviral for the prevention and treatment of influenza patients infected with H5N1 or other subtype viruses. Introduction Human H1N1 and H3N2 influenza A viruses are highly contagious and cause seasonal influenza worldwide. spread across several continents and caused epidemics with high morbidity and mortality. We demonstrated that R-125489 interferes with the NA activity of H5N1 viruses, including oseltamivir-resistant and different clade strains. A single Pomalidomide (CC-4047) dose of CS-8958 (1,500 g/kg) given to mice 2 h post-infection with H5N1 influenza viruses produced a higher survival rate Pomalidomide (CC-4047) than did continuous five-day administration of oseltamivir (50 mg/kg twice daily). Virus titers in lungs and brain were substantially lower in infected mice treated with a single dose of CS-8958 than in those treated with the five-day course of oseltamivir. CS-8958 was also highly efficacious against highly pathogenic H5N1 influenza virus and oseltamivir-resistant variants. A single dose of CS-8958 given seven days prior to virus infection also protected mice against H5N1 virus lethal infection. To evaluate the improved efficacy of CS-8958 over oseltamivir, the binding stability of R-125489 to various subtypes of influenza virus was assessed and compared with that of other NA inhibitors. We found that R-125489 bound to NA more tightly than did any other NA inhibitor tested. Our results indicate that CS-8958 is highly effective for the treatment and prophylaxis of infection with H5N1 influenza viruses, including oseltamivir-resistant mutants. Author Summary Since the first human outbreak in Hong Kong in 1997, highly pathogenic H5N1 avian influenza A viruses have posed a threat to public health. Because some isolates exhibit resistance to oseltamivir, a WHO-recommended neuraminidase (NA) inhibitor for the treatment of H5N1 influenza infection, alternative antivirals are urgently needed. Here, we assessed the efficacy of CS-8958, a prodrug of the novel neuraminidase Pomalidomide (CC-4047) inhibitor R-125489, against highly pathogenic H5N1 influenza viruses in a murine lethal infection model. We found that CS-8958 confers more potent and long-lasting protection to mice against H5N1 influenza viruses, including oseltamivir-resistant mutants, than does oseltamivir. Further, we demonstrate that CS-8958 has substantial efficacy as both a therapeutic and a prophylactic agent against H5N1 influenza viruses in mice. CS-8958 is, therefore, a Pomalidomide (CC-4047) promising candidate antiviral for the prevention and treatment of influenza patients infected with H5N1 or other subtype viruses. Introduction Human H1N1 and H3N2 influenza A viruses are highly contagious and cause seasonal influenza worldwide. The global impact of influenza epidemics is Pomalidomide (CC-4047) estimated to be 3.5 million cases of severe illness and 300,000 to 500,000 deaths annually . The elderly, young children, and immunocompromised patients are particularly at risk, with substantial morbidity and mortality among these groups . In addition, the emergence of a virus possessing hemagglutinin and neuraminidase (NA) to which humans have limited immunological memory creates the potential for pandemic influenza. In 1997, human infections with highly pathogenic H5N1 avian influenza viruses were first documented in Hong Kong C. Since then, these viruses have spread throughout Asia, Europe, and Africa with high morbidity and mortality among avian species and with occasional transmission to humans with high mortality (http://www.who.int/csr/disease/avian_influenza/en/). Although human-to-human transmission is rare, once the H5N1 viruses acquire this ability, a devastating pandemic may be inevitable. Two countermeasures are available to control human influenza: vaccination and antiviral treatment. Although vaccination plays a critical role in influenza prophylaxis, it takes more than six months to produce sufficient vaccine to cover a large proportion of the human population upon the emergence of a new strain . Therefore, antivirals are important tool to mitigate an influenza pandemic. Currently, two types of anti-influenza drug are available: M2 ion channel blockers (amino-adamantines; amantadine and rimantadine)  and NA inhibitors (oseltamivir and zanamivir) . However, amino-adamantine-resistant viruses readily emerge and are already prevalent worldwide among the seasonal influenza viruses (both H1N1 and H3N2 subtypes ,). In fact, the Rabbit polyclonal to DUSP14 recently emerged swine-origin pandemic (H1N1) 2009 virus is already amino-adamantine-resistant . Moreover, the emergence of amino-amantadine-resistant H5N1 viruses in Vietnam,.