Journal of Medicinal Chemistry p. 6346 - 6362 (2019)
Update date:2022-08-16
Topics:
Yoon, Ji-Seong
Kim, Gyudong
Jarhad, Dnyandev B.
Kim, Hong-Rae
Shin, Young-Sup
Qu, Shuhao
Sahu, Pramod K.
Kim, Hea Ok
Lee, Hyuk Woo
Wang, Su Bin
Kong, Yun Jeong
Chang, Tong-Shin
Ogando, Natacha S.
Kovacikova, Kristina
Snijder, Eric J.
Posthuma, Clara C.
Van Hemert, Martijn J.
Jeong, Lak Shin
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.
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