Inhibition of enterovirus 71 by adenosine analog NITD008

Deng CL, Yeo H, Ye HQ, Liu SQ, Shang BD, Gong P, Alonso S, Shi PY, Zhang B. 

J Virol. 2014 Aug 6. pii: JVI.01207-14.

Abstract 

　　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 a potent antiviral activity against EV71. In cell culture, the compound inhibits EV71 with an EC50 of 0.67 μM and CC50 of 119.97 μM. When dosed at 5 mg/kg in an EV71 mouse model, the compound reduced viral load 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 concentration of NITD008. Resistance mutations were reproducibly mapped to viral 3A and 3D polymerase regions. Resistance analysis using recombinant viruses demonstrated that either 3A or 3D mutation alone could lead to resistance to NITD008. Combination of both 3A and 3D mutations conferred higher resistance, suggesting a collaborative interplay between 3A and 3D proteins during viral replication. The resistance results underline the importance of combination therapy required for EV71 treatment. 

      SIGNIFICANCE: 

　　Human enterovirus 71 (EV71) has emerged as a major cause of viral encephalitis in children worldwide, especially in the Asia-Pacific regions. 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) to inhibit EV71. The efficacy results validated that nucleoside analogs have potential as antiviral drugs for EV71 infections. Mechanistically, we showed that mutations in viral 3A and 3D polymerase 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 for combination therapy for treatment of EV71 infections. 

http://jvi.asm.org/content/early/2014/07/31/JVI.01207-14.short