Design, Synthesis, and Anti-RNA Virus Activity of 6′-Fluorinated-Aristeromycin Analogues

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 N6-methyladenosine
analogues 2a–e showed potent inhibition against
SAH hydrolase, while only the adenosine derivatives 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) showed the strongest antiviral effect for MERS-CoV, with a ∼2.5
log reduction in infectious progeny titer in viral load reduction
assay. The phosphoramidate prodrug 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.