Novel AR-12 derivatives, P12-23 and P12-34, inhibit flavivirus replication by blocking host de novo pyrimidine biosynthesis. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Yang, Chao-Fu; Gopula, Balraj; Liang, Jian-Jong; Li, Jin-Kun; Chen, Si-Yu; Lee, Yi-Ling; Chen, Ching; Lin, Yi-Ling
• Is Part Of: Emerging microbes & infections. Volume 7:Issue 1(2018)
• Page Start: 1
• Page End: 11
• Publication Date: 2018-12
• Subjects: Medical microbiology -- Periodicals; Communicable diseases -- Periodicals; Infection -- Periodicals; 616.9041
• DOI: 10.1038/s41426-018-0191-1
• Languages: English
• ISSNs: 2222-1751

Abstract

Abstract The genusFlavivirus contains many important pathogens, including dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV). AR-12 is a celecoxib-derived anticancer agent that possesses antiviral activity against a broad range of viruses. We pharmacologically exploited this unique activity to develop additional antiviral agents, resulting in the production of the AR-12 derivatives P12-23 and P12-34. At nanomolar concentrations, these compounds were effective in suppressing DENV, ZIKV and JEV replication, exhibiting 10-fold improvements in the efficacy and selectivity indices as compared to AR-12. Regarding the mode of antiviral action, P12-23 and P12-34 inhibited viral RNA replication but had no effect on viral binding, entry or translation. Moreover, these AR-12 derivatives co-localized with mitochondrial markers, and their antiviral activity was lost in mitochondria-depleted cells. Interestingly, exogenous uridine or orotate, the latter being a metabolite of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), abolished the antiviral activity of AR-12 and its derivatives. As DHODH is a key enzyme in the de novo pyrimidine biosynthesis pathway, these AR-12 derivatives may act by targeting pyrimidine biosynthesis in host cells to inhibit viral replication. Importantly, treatment with P12-34 significantly improved the survival of mice that were subcutaneously challenged with DENV. Thus, P12-34 may warrant further evaluation as a therapeutic to control flaviviral outbreaks.