ArticleEmerging microbes & infections2018
Novel AR-12 derivatives, P12-23 and P12-34, inhibit flavivirus replication by blocking host de novo pyrimidine biosynthesis.
Article in Emerging microbes & infections, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 46 citations in OpenAlex.
- Novel and repurposed antiviral molecules for arbovirus infections with epidemic Potential: A systematic review.New microbes and new infections · 2025Review
- A Comprehensive Review of the Development and Therapeutic Use of Antivirals in Flavivirus Infection.Viruses · 2025Review
- The endoplasmic reticulum (ER): a crucial cellular hub in flavivirus infection and potential target site for antiviral interventions.Npj viruses · 2024Review
- Classical swine fever virus non-structural protein 4A recruits dihydroorotate dehydrogenase to facilitate viral replication.Journal of virology · 2024Article
- Review
- Vidofludimus inhibits porcine reproductive and respiratory syndrome virus infection by targeting dihydroorotate dehydrogenase.Veterinary research · 2023Article
- Human ACE2 protein is a molecular switch controlling the mode of SARS-CoV-2 transmission.Journal of biomedical science · 2023Article
- Vector-Transmitted Flaviviruses: An Antiviral Molecules Overview.Microorganisms · 2023Review
- Review
- Review
- Regulation of the pyrimidine biosynthetic pathway by lysine acetylation of E. coli OPRTase.The FEBS journal · 2023Article
- Inhibitors of Nucleotide Biosynthesis as Candidates for a Wide Spectrum of Antiviral Chemotherapy.Microorganisms · 2022Review
- Finding a chink in the armor: Update, limitations, and challenges toward successful antivirals against flaviviruses.PLoS neglected tropical diseases · 2022Review
- Development of accelerated high-throughput antiviral screening systems for emerging orthomyxoviruses.Antiviral research · 2022Article
- Inhibition of mitochondrial complex III or dihydroorotate dehydrogenase (DHODH) triggers formation of poly(A)RNA biology · 2022Article
- Celecoxib Analogues for Cancer Treatment: An Update on OSU-03012 and 2,5-Dimethyl-Celecoxib.Biomolecules · 2021Review
- DHODH and cancer: promising prospects to be explored.Cancer & metabolism · 2021Review
- Convenient Auto-Processing Vector Based on Bamboo Mosaic Virus for Presentation of Antigens Through Enzymatic Coupling.Frontiers in immunology · 2021Article
- Article
- Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.Cell chemical biology · 2020Article
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
The genus Flavivirus 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.