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Metformin inhibits EV-A71 and CVA16 infections by regulating TRIB3-SCARB2 axis and activating AMPK

Huiqiang Wang1, Boming Cui1, Haiyan Yan1

  • 1CAMS Key Laboratory of Antiviral Drug Research, Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Antiviral Research
|January 18, 2025
PubMed

Insights

Metformin inhibits enterovirus A71 (EV-A71) and Coxsackievirus A16 (CVA16) replication by targeting tribbles 3 (TRIB3) and AMP-activated protein kinase (AMPK). This drug shows promise as an antiviral agent against enterovirus infections in mice.

Area of Science:

  • Virology
  • Molecular Biology
  • Pharmacology

Background:

  • Tribbles 3 (TRIB3) facilitates enterovirus A71 (EV-A71) infection by increasing the EV-A71 receptor, scavenger receptor class B member 2 (SCARB2).
  • Metformin is known to down-regulate TRIB3 expression, suggesting its potential as an antiviral therapeutic.

Purpose of the Study:

  • To investigate the antiviral potential of metformin against EV-A71 and Coxsackievirus A16 (CVA16).
  • To elucidate the mechanisms underlying metformin's antiviral activity, including its role concerning TRIB3 and AMP-activated protein kinase (AMPK).

Main Methods:

  • Assessing metformin's effect on EV-A71 and CVA16 replication in vitro.
  • Investigating the impact of metformin on TRIB3 transcription and SCARB2 protein levels.
  • Examining the role of AMPK activation in metformin's antiviral action using AICAR and Compound C.
  • Evaluating metformin's efficacy in a mouse model of lethal EV-A71 infection.

Main Results:

  • Metformin inhibited EV-A71 and CVA16 replication by down-regulating TRIB3 transcription and consequently reducing SCARB2 protein levels.
  • Metformin also exhibited TRIB3-independent antiviral activity through the activation of AMPK.
  • AMPK activation was confirmed as a key mechanism for metformin's antiviral effect, as inhibiting AMPK reversed its action.
  • Metformin treatment protected mice from lethal EV-A71 infection, reducing viral load and improving muscle pathology.

Conclusions:

  • TRIB3 is a viable target for antiviral drug development against enteroviruses.
  • Metformin demonstrates significant potential as an antiviral agent or supplement for enterovirus infections, acting through both TRIB3-dependent and TRIB3-independent pathways involving AMPK activation.
Keywords:
AMPKCoxsackievirus A16Enterovirus A71MetforminSCARB2TRIB3

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