In vitro and in vivo Antiviral Activity of the Acyclic Nucleoside Phosphonate Prodrug LAVR-289 against Poxvirus and African Swine Fever Virus Replication

Poxviruses are double-stranded DNA viruses including relevant zoonotic pathogens with high morbidity. Although African swine fever virus (ASFV) belongs to the Asfarviridae family and is not strictly classified as a member of the Poxviridae, both fall within the same class of Pokkesviricetes that replicate in the cytoplasm, and some poxviruses pose potential biological warfare threats. Among compounds targeting these viruses, acyclic nucleoside phosphonate prodrugs are nucleoside analogues inhibitors of viral DNA polymerases that have been identified as promising agents. However, some limitations related to their toxicity and the rapid emergence of resistance highlight the need for new antiviral molecules. In this study, the new nucleoside analogue LAVR-289 was shown to effectively inhibit the viral replication by intervening early in the viral replication step, targeting a specific domain of the poxvirus DNA polymerase. Using monkeypox virus models, the subcutaneous or oral administration of LAVR-289 demonstrates protective efficacy in infected animal models without toxicity or behavioral modification. The stability in vivo, long shelf-life and efficacy make LAVR-289 a promising candidate for further development and stockpiling as a medical countermeasure against dsDNA virus outbreaks. Its broad-spectrum efficacy is a real asset in a context of recurrent viral epidemics, risk of bioterrorism and emergence of resistance strains in the population. HighlightsO_LILAVR-289 is a unique acyclic nucleoside phosphonate prodrug targeting viral DNA polymerases. C_LIO_LILAVR-289 displays antiviral activity against dsDNA viruses, ASFV and poxviruses. C_LIO_LIFirst report of in vivo evaluation of LAVR-289 against MPXV by subcutaneous and oral administration. C_LIO_LILAVR-289 reduces clinical signs and increase survival in animal models. C_LI