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Inhibition of enterovirus 71 by adenosine analog NITD008
#MMPMID25100827
Deng CL
; Yeo H
; Ye HQ
; Liu SQ
; Shang BD
; Gong P
; Alonso S
; Shi PY
; Zhang B
J Virol
2014[Oct]; 88
(20
): 11915-23
PMID25100827
show ga
Enterovirus 71 (EV71) is a major viral pathogen in China and Southeast Asia.
There is no clinically approved vaccine or antiviral therapy for EV71 infection.
NITD008, an adenosine analog, is an inhibitor of flavivirus that blocks viral RNA
synthesis. Here we report that NITD008 has potent antiviral activity against
EV71. In cell culture, the compound inhibits EV71 at a 50% effective
concentration of 0.67 ?M and a 50% cytotoxic concentration of 119.97 ?M. When
administered at 5 mg/kg in an EV71 mouse model, the compound reduced viral loads
in various organs and completely prevented clinical symptoms and death. To study
the antiviral mechanism and drug resistance, we selected escape mutant viruses by
culturing EV71 with increasing concentrations of NITD008. Resistance mutations
were reproducibly mapped to the viral 3A and 3D polymerase regions. Resistance
analysis with recombinant viruses demonstrated that either a 3A or a 3D mutation
alone could lead to resistance to NITD008. A combination of both 3A and 3D
mutations conferred higher resistance, suggesting a collaborative interplay
between the 3A and 3D proteins during viral replication. The resistance results
underline the importance of combination therapy required for EV71 treatment.
Importance: Human enterovirus 71 (EV71) has emerged as a major cause of viral
encephalitis in children worldwide, especially in the Asia-Pacific region.
Vaccines and antivirals are urgently needed to prevent and treat EV71 infections.
In this study, we report the in vitro and in vivo efficacy of NITD008 (an
adenosine analog) as an inhibitor of EV71. The efficacy results validated the
potential of nucleoside analogs as antiviral drugs for EV71 infections.
Mechanistically, we showed that mutations in the viral 3A and 3D polymerases
alone or in combination could confer resistance to NITD008. The resistance
results suggest an intrinsic interaction between viral proteins 3A and 3D during
replication, as well as the importance of combination therapy for the treatment
of EV71 infections.
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