An adenosine nucleoside analogue NITD008 inhibits EV71 proliferation

Area of Science:

• Virology
• Drug Discovery
• Molecular Biology

Background:

• Enterovirus 71 (EV71) is a major cause of Hand-Foot-Mouth Disease (HFMD), posing a significant public health threat.
• Effective antiviral therapies for EV71 infections are limited.
• Nucleoside analogues are a proven class of antiviral agents.

Purpose of the Study:

• To identify effective antiviral compounds against Enterovirus 71.
• To evaluate the antiviral activity of nucleoside analogues against EV71.
• To elucidate the mechanism of action of promising compounds.

Main Methods:

• Screening of 27 nucleoside analogues for anti-EV71 activity in cell culture.
• Determining the selectivity index of active compounds.
• Investigating the mechanism of action, including inhibition of RNA-dependent RNA polymerase and VPg uridylylation.
• Assessing synergistic effects with other antiviral agents.

Main Results:

• NITD008, an adenosine nucleoside analogue, demonstrated potent inhibition of diverse EV71 strains in RD, 293T, and Vero cells.
• Triphosphorylated NITD008 (ppp-NITD008) acts as a chain terminator, directly inhibiting EV71 RNA-dependent RNA polymerase activity.
• NITD008 did not interfere with the EV71 VPg uridylylation process.
• A significant synergistic effect was observed between NITD008 and rupintrivir (a protease inhibitor).

Conclusions:

• NITD008 is a potent inhibitor of Enterovirus 71 replication with a high selectivity index.
• The mechanism involves direct inhibition of viral RNA-dependent RNA polymerase.
• Combination therapy with NITD008 and other antivirals like rupintrivir shows promise for treating EV71 infections.