Tenovin-1 inhibited dengue virus replication through SIRT2

Area of Science:

• Virology
• Pharmacology
• Immunology

Background:

• Dengue fever is a widespread arbovirus disease with no effective treatments or safe vaccines.
• Sirtuins (SIRTs) are implicated in dengue virus infection.
• There is an urgent need for novel antiviral agents against dengue virus.

Purpose of the Study:

• To investigate the antiviral potential of tenovin-1, a SIRT1/2 inhibitor, against dengue virus (DENV).
• To elucidate the mechanism of action of tenovin-1 in inhibiting DENV replication and associated inflammatory responses.

Main Methods:

• In vitro antiviral assays using BHK-21 cells infected with DENV.
• Drug-addition assays to determine the stage of antiviral action.
• Measurement of viral protein and mRNA levels.
• Assessment of inflammatory cytokine release.
• Experiments involving SIRT agonists and SIRT2 knockdown.

Main Results:

• Tenovin-1 demonstrated significant antiviral activity against all four DENV serotypes in vitro, with EC50 values ranging from 0.97 to 3.81 μM.
• Tenovin-1 treatment reduced viral cytopathic effects, inhibited progeny virus release, and decreased viral protein and mRNA levels.
• The compound acts post-viral infection and reduces inflammatory responses by lowering cytokine release.
• The antiviral effect was confirmed to be on-target, as it was abrogated by SIRT agonists or SIRT2 knockdown.

Conclusions:

• Tenovin-1 exhibits potent antiviral activity against dengue virus through inhibition of SIRT2.
• Tenovin-1 also modulates the inflammatory response during DENV infection.
• This compound represents a promising therapeutic candidate for flavivirus infections and warrants further investigation.