A broad-spectrum antiviral targeting entry of enveloped viruses

TLDR

The study reports LJ001, a small‑molecule antiviral that inhibits a broad range of enveloped viruses such as influenza, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV‑1. LJ001 acts by intercalating into viral lipid membranes, irreversibly disabling virions while preserving envelope proteins, and blocking virus–cell fusion downstream of attachment but upstream of membrane merger, with its activity dependent on both polar and nonpolar moieties. The compound showed no toxicity, was ineffective against nonenveloped viruses, and protected animals from lethal Ebola and Rift Valley fever infections, demonstrating a broad‑spectrum antiviral that targets viral membranes.

Abstract

We describe an antiviral small molecule, LJ001, effective against numerous enveloped viruses including Influenza A, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV-1. In sharp contrast, the compound had no effect on the infection of nonenveloped viruses. In vitro and in vivo assays showed no overt toxicity. LJ001 specifically intercalated into viral membranes, irreversibly inactivated virions while leaving functionally intact envelope proteins, and inhibited viral entry at a step after virus binding but before virus–cell fusion. LJ001 pretreatment also prevented virus-induced mortality from Ebola and Rift Valley fever viruses. Structure–activity relationship analyses of LJ001, a rhodanine derivative, implicated both the polar and nonpolar ends of LJ001 in its antiviral activity. LJ001 specifically inhibited virus–cell but not cell–cell fusion, and further studies with lipid biosynthesis inhibitors indicated that LJ001 exploits the therapeutic window that exists between static viral membranes and biogenic cellular membranes with reparative capacity. In sum, our data reveal a class of broad-spectrum antivirals effective against enveloped viruses that target the viral lipid membrane and compromises its ability to mediate virus–cell fusion.