<i>In Vitro</i> and <i>Ex Vivo</i> evidence that pharmacological induction of the hypoxia response pathway efficiently restricts measles and Nipah virus infections

Airborne RNA viruses of the <i>Paramyxoviridae</i> family are major human pathogens. These include measles virus (MeV) and Nipah virus (NiV), the latter being on the World Health Organization's blueprint list due to its high case-fatality rate and critical risk of emergence. Although an effective vaccine is available for MeV, this is not the case for NiV. Moreover, there is no cure for MeV- or NiV-infected patients that prevents the acute respiratory syndrome or lethal encephalitis. To identify new host factors to target for inhibiting viral growth, a library of metabolic modulators was screened for activity against MeV using an <i>in vitro</i> infection model. Results showed that Molidustat, a pharmacological inhibitor of Prolyl-Hydroxylase Domain (PHD) enzymes, inhibits MeV infection in a Hypoxia-Inducible Factor (HIF)-dependent manner. We then tested the antiviral effect of Molidustat in organotypic cultures of hamster cerebellum. Molidustat induced the hypoxia-response pathway in this <i>ex vivo</i> model as assessed by transcriptomic analysis, and inhibited MeV infection. A similar antiviral effect was observed with Roxadustat and Daprodustat, two PHD enzyme inhibitors chemically unrelated to Molidustat. Finally, we showed that Molidustat inhibits NiV infection in organotypic cultures of hamster cerebellum and lung, thereby validating its effect in the two organs mainly targeted during infection. Taken together, our results provide evidence that pharmacological activation of the hypoxia-response pathway restricts MeV and NiV infections, highlighting HIF-inducing drugs as promising candidates to consider in the development of treatments.