Novel quinolone derivatives targeting human dihydroorotate dehydrogenase suppress Ebola virus infection in vitro

Ebola virus (EBOV) has emerged as a significant public health concern since the 2013-2016 outbreak in West Africa. Currently, no effective antiviral treatments have been approved for clinical use. Compound 1 RYL-634 is a quinolone-derived compound that can inhibit dihydroorotate dehydrogenase, a rate-limiting enzyme in the de novo pyrimidine synthesis pathway and it exhibited antiviral activity against multiple RNA virus infection. In this study, we evaluated the efficacy of a panel of newly developed compounds based on RYL-634 against EBOV infection. Our data showed that RYL-634 as well as its derivatives are effective against EBOV transcription-and replication-competent virus-like particle (trVLP) infection and authentic EBOV infection in vitro at low nano-molar IC50 values and relatively high CC50. Of note, the new derivative RYL-687 had the lowest IC50 at approximately 7 nM and was almost 6 times more potent than remdesivir (GS-5734). Exogenous addition of different metabolites in the pyrimidine de novo synthesis pathway confirmed DHODH as the target of RYL-687. These data provide evidence that such quinolone-derived compounds are promising therapeutic candidates against EBOV infection.

Automated summary

RYL-634 and its derivatives show effective inhibition against EBOV infection, with the new derivative RYL-687 demonstrating the lowest IC50 and being almost 6 times more potent than remdesivir. These quinolone-derived compounds are promising therapeutic candidates against EBOV infection.