In vitro and in vivo efficacy of a novel nucleoside analog H44 against Crimean–Congo hemorrhagic fever virus

Crimean–Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus that causes fever, hemorrhage, and multi-organ failure, with an average fatality rate of ∼40% in humans. Currently, there are no available vaccines or drugs for the treatment of Crimean–Congo hemorrhagic fever (CCHF). Favipiravir (T-705), a nucleoside analog, protects against CCHFV infection in animal models. Here, we evaluated the anti-CCHFV efficacy of several nucleoside analogs, including some well-known compounds such as remdesivir (GS-5734), EIDD-1931 and its prodrug molnupiravir (EIDD-2801), as well as a novel T-705-derived compound H44. T-705, H44, and EIDD-1931 inhibited CCHFV infection in vitro while GS-5734 had no inhibitory effect. All three nucleoside analogs functioned at the “post-entry” stage of virus infection. However, EIDD-2801 failed to protect type I interferon receptor knockout (IFNAR)−/− mice from CCHFV infection. H44, similar to T-705, conferred 100% protection to IFNAR−/− mice against lethal CCHFV challenge, even with delayed administration. This study provided in vitro and in vivo data regarding the anti-CCHFV efficacy of different nucleosides and identified a novel compound, H44, as a promising drug candidate for the treatment of CCHFV infection in vivo. •H44, T-705, and EIDD-1931 inhibited CCHFV infection in vitro while GS-5734 did not.•H44, T-705, and EIDD-1931 inhibited CCHFV infection at the “post-entry” stage.•EIDD-2081, the EIDD-1931 prodrug, did not protect IFNAR−/− mice from CCHFV infection.•H44 protected IFNAR−/− mice from lethal CCHFV challenge as efficiently as T-705.