Voxtalisib inhibits enterovirus 71 replication by downregulating host RAN and restoring IFN-STAT signaling

Area of Science:

• Virology
• Immunology
• Pharmacology

Background:

• Hand, Foot, and Mouth Disease (HFMD) is a common childhood illness caused by enteroviruses, with Enterovirus 71 (EV71) linked to severe neurological complications.
• Current treatments lack specific antiviral therapies with defined mechanisms, and host-targeting strategies are underexplored.
• Voxtalisib, a dual PI3K/mTOR inhibitor, was identified as a potential inhibitor of EV71 replication, but its mechanism was unclear.

Purpose of the Study:

• To discover novel host-targeted antiviral candidates.
• To elucidate the antiviral mechanism of voxtalisib against EV71 and other enteroviruses.

Main Methods:

• Phenotypic screening identified voxtalisib as an anti-EV71 compound.
• Proteomic analysis in RD cells revealed Ras-related nuclear protein (RAN) as a key host factor.
• In vivo studies in mice assessed voxtalisib's efficacy against EV71, Coxsackie B viruses, and Echovirus 11.

Main Results:

• EV71 infection upregulated RAN; voxtalisib suppressed RAN, inhibiting viral replication.
• RAN regulates nuclear-cytoplasmic transport of phosphorylated STAT1/2 (p-STAT1/2), impacting interferon-mediated antiviral responses.
• Voxtalisib treatment improved survival, reduced viral loads, and alleviated organ damage in EV71-infected mice, demonstrating broad-spectrum potential.

Conclusions:

• Ras-related nuclear protein (RAN) is a novel host target that regulates p-STAT1/2 transport and influences enterovirus replication.
• Voxtalisib restores interferon-STAT signaling by modulating RAN, presenting a promising host-directed antiviral strategy.
• This approach shows potential against a range of enteroviruses, including EV71, CVB, and Echo11.