1. Design, Synthesis, and Anti-RNA Virus Activity of 6'-Fluorinated-Aristeromycin Analogues.
- Author
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Yoon JS, Kim G, Jarhad DB, Kim HR, Shin YS, Qu S, Sahu PK, Kim HO, Lee HW, Wang SB, Kong YJ, Chang TS, Ogando NS, Kovacikova K, Snijder EJ, Posthuma CC, van Hemert MJ, and Jeong LS
- Subjects
- Adenosine chemical synthesis, Adenosine pharmacology, Adenosylhomocysteinase antagonists & inhibitors, Animals, Antiviral Agents chemical synthesis, Chlorocebus aethiops, Drug Design, Enzyme Inhibitors chemical synthesis, Halogenation, Humans, Molecular Structure, Prodrugs chemical synthesis, Prodrugs pharmacology, RNA-Dependent RNA Polymerase antagonists & inhibitors, Vero Cells, Adenosine analogs & derivatives, Antiviral Agents pharmacology, Enzyme Inhibitors pharmacology, RNA Viruses drug effects
- Abstract
The 6'-fluorinated aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell S -adenosyl-l-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6'-position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and N
6 -methyladenosine analogues 2a-e exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6',6'-Difluoroaristeromycin ( 2a-c exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6',6'-Difluoroaristeromycin ( 2c also demonstrated potent broad-spectrum antiviral activity, possibly by inhibiting the viral RdRp. This study shows that 6'-fluorinated aristeromycins can serve as starting points for the development of broad-spectrum antiviral agents that target RNA viruses.3a also demonstrated potent broad-spectrum antiviral activity, possibly by inhibiting the viral RdRp. This study shows that 6'-fluorinated aristeromycins can serve as starting points for the development of broad-spectrum antiviral agents that target RNA viruses.- Published
- 2019
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