IR415, a Potent Anti-HBV Agent , Selectively Targets HBx

IR415, a Potent Anti-HBV Agent , Selectively Targets HBx

Hepatitis B is a serious infectious disease of the human liver caused by the hepatitis B virus (HBV). Meanwhile, HBV infection often becomes chronic. It results in hepatocellular carcinoma (HCC). In susceptible host cells, HBV generates a favorable environment for its replication and escapes the innate immune system, including the RNAi-mediated defense of the host cell. RNA-mediated gene silencing acts as a robust inducible defense mechanism to protect the host from viral invasion and establishment. HBx is a viral suppressor that confers counterdefense strategy. Hepatitis B X protein acts as a multifunctional regulator to induce HBx-responsive transcription factors like NF-κB and NF-AT.  Several studies address the role of HBx by targeting it using either short hairpin RNAs (shRNAs) or siRNA for the cessation of HBV replication. In this study, IR415 is a potent anti-HBV agent and inhibits HBV replication by blocking the HBx activity.

IR415 a potent Anti HBV Agent Selectively Targets HBx 2020 05 20 - IR415, a Potent Anti-HBV Agent , Selectively Targets HBx

IR415 selectively interacts with HBx (Kd=2 nM) and blocks HBV-mediated RNAi suppression, reverses the inhibitory effect of HBx protein on the activity of the dicer endoribonuclease. It has a dose-dependent inhibitory effect on HBx, with a minimal effective concentration of 50 μM. Furthermore, IR415 effectively blocks the HBx-mediated GFP expression. It also shows the predicted ability to bind to the HBx α-helix. In addition, IR415 blocks the suppressor activity of HBx and allows siRNA biogenesis.

In summary, IR415 blocks HBx-mediated RNAi suppression. It reverses the inhibitory effect of HBx protein on the activity of the Dicer endoribonuclease. Therefore, it provides evidence for the antiviral function of host RNAi machinery in HBV replication and identifies a pharmacophore that binds and blocks HBx activity.

Reference:

Ghosh S, et al.J Biol Chem. 2017 Jul 28;292(30):12577-12588.

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