Novel dihydroorotate dehydrogenase inhibitors with potent interferon-independent antiviral activity against mammarenaviruses in vitro

Abstract

Mammarenaviruses cause chronic infections in rodents,which are their predominant natural hosts. Human infectionwith some of these viruses causes high-consequence disease, posing significant issues in publichealth. Currently, noFDA-licensedmammarenavirusvaccines are available, andanti-mammarenavirus drugs are limited to an off-label use of ribavirin,which is only partially efficacious and associatedwith severe sideeffects. Dihydroorotatedehydrogenase(DHODH) inhibitors,whichblockdenovopyrimidinebiosynthesis, have antiviral activity against viruses fromdifferent families, including Arenaviridae, the taxonomic home ofmammarenaviruses. Here,we evaluate five novel DHODHinhibitors for their antiviral activity against mammarenaviruses. All testedDHODHinhibitorswerepotently active against lymphocytic choriomeningitis virus (LCMV) (half-maximal effective concentrations [EC50] in the lownanomolar range, selectivity index [SI] > 1000). The tested DHODHinhibitors did not affect virion cell entry or budding, but rather interfered with viral RNA synthesis. This interference resulted in a potent interferon-independent inhibition of mammarenavirusmultiplication in vitro, including the highly virulent Lassa and Junín viruses.