1. Novel quinolone derivatives targeting human dihydroorotate dehydrogenase suppress Ebola virus infection in vitro.
- Author
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Gong M, Yang Y, Huang Y, Gan T, Wu Y, Gao H, Li Q, Nie J, Huang W, Wang Y, Zhang R, Zhong J, Deng F, Rao Y, and Ding Q
- Subjects
- Adenosine Monophosphate analogs & derivatives, Adenosine Monophosphate pharmacology, Africa, Western, Alanine analogs & derivatives, Alanine pharmacology, Cell Line, Hemorrhagic Fever, Ebola drug therapy, Humans, Inhibitory Concentration 50, Quinolones chemistry, Antiviral Agents pharmacology, Dihydroorotate Dehydrogenase antagonists & inhibitors, Ebolavirus drug effects, Quinolones pharmacology, Virus Replication drug effects
- Abstract
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 nanomolar IC
50 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)- Published
- 2021
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