American Chemical Society
Browse
jm9b00781_si_003.csv (1.91 kB)

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

Download (1.91 kB)
Version 2 2020-02-24, 13:55
Version 1 2019-06-19, 21:14
dataset
posted on 2020-02-24, 13:55 authored by Ji-seong Yoon, Gyudong Kim, Dnyandev B. Jarhad, Hong-Rae Kim, Young-Sup Shin, Shuhao Qu, Pramod K. Sahu, Hea Ok Kim, Hyuk Woo Lee, Su Bin Wang, Yun Jeong Kong, Tong-Shin Chang, Natacha S. Ogando, Kristina Kovacikova, Eric J. Snijder, Clara C. Posthuma, Martijn J. van Hemert, Lak Shin Jeong
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.

History