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Dr. Lin, Yi-Ling

Distinguished Research Fellow
Division Chief
  • 02-2789-9013 (Lab) (Room No: 443)
  • 02-2652-3902
  • 02-2785-8847 (Fax)

  • Molecular Virology
  • Viral Pathogenesis
  • Viral Immunology

Education and Positions:
  • 1992, PhD, University of California, Los Angeles (UCLA), USA

    2020 ~ date, CEO, Emerging Infectious Disease Division (EIDD), Biomedical Translation Research Center (BioTReC), Academia Sinica


    Contact Information:

Highlight Detail

Novel AR-12 derivatives, P12-23 and P12-34, inhibit flavivirus replication by blocking host de novo pyrimidine biosynthesis

Dr. Lin, Yi-Ling
Emerging Microbes & Infections, Nov 21, 2018

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.