LAVR-289, a New Orally Bioavailable Inhibitor of Adenovirus Replication in vitro and in vivo.

Abstract

Adenoviruses are responsible for a range of pathologies, including respiratory infections in children, accounting for 5-10% of such cases. Although most adenovirus infections are self-resolving, they can cause serious illness, particularly in immunocompromised individuals. There is currently no approved treatment for adenovirus infections, although various therapeutic approaches are under investigation, including nucleoside analog inhibitors of replication. However, these treatments have shown limited efficacy. In this study, we report on the antiviral activity of LAVR-289, a broad-spectrum acyclonucleoside phosphonate exhibiting potent in vitro efficacy against several adenovirus serotypes, comparable to that of brincidofovir. LAVR-289 specifically inhibits viral replication, blocking the formation of viral replication centers and preventing late protein expression without affecting viral entry or delivery of viral genomes to the nucleus. In vivo using immunocompromised Syrian hamsters infected with HAdV-C6, oral administration of LAVR-289 resulted in 100% animal survival. These results suggest that LAVR-289 holds promise as a potential therapy for adenovirus infections, particularly in immunocompromised patients. HighlightsO_LILAVR-289 is a unique acyclic nucleoside phosphonate prodrug. C_LIO_LILAVR-289 displays antiviral activity against Adenovirus with an EC50 of about 100 nM against HAdV-C5 ANCHOR. C_LIO_LILAVR-289 inhibits viral replication by targeting viral DNA polymerase, preventing DBP clustering and replication center formation. C_LIO_LIIn immunosuppressed Syrian hamsters, LAVR-289 is well tolerated and ensures 100% survival while effectively stopping virus replication. C_LIO_LILAVR-289's broad-spectrum activity positions it as a promising treatment for immunocompromised patients facing multiple viral infections. C_LI