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MMF inhibits poxvirus infection by disrupting IMPDH2 interaction with USP5 and inducing its rod-and-ring assemblies

Qian Sun1, Kesen Liu2, Wandi Cao2

  • 1School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518060, China.

Virologica Sinica
|July 23, 2026
PubMed

Insights

Mycophenolate mofetil effectively inhibits monkeypox virus (MPXV) and vaccinia virus (VACV) replication by targeting host nucleotide metabolism. This host-directed strategy offers a promising therapeutic approach for orthopoxvirus infections.

Area of Science:

  • Virology
  • Drug Discovery
  • Molecular Biology

Background:

  • Monkeypox virus (MPXV) is a global health threat, with limited therapeutic options due to antiviral resistance and availability issues.
  • Targeting host nucleotide metabolism is a promising strategy for broad-spectrum antiviral development.
  • Vaccinia virus (VACV) serves as a suitable surrogate for MPXV due to genetic and biological similarities.

Purpose of the Study:

  • To identify novel MPXV inhibitors by screening FDA-approved drugs targeting nucleotide metabolism enzymes.
  • To evaluate the antiviral efficacy of identified compounds against MPXV and VACV.
  • To elucidate the mechanism of action for potential drug candidates.

Main Methods:

  • Screening of 10 FDA-approved nucleotide metabolism inhibitors using VACV as a surrogate model.
  • In vitro antiviral assays to determine inhibition effects against VACV and MPXV.
  • Time-course studies to identify the stage of viral replication targeted by MMF.
  • Mechanistic studies involving IMPDH2 activity, USP5, and R&R assembly.

Main Results:

  • Mycophenolate mofetil (MMF), an IMPDH2 inhibitor, showed potent inhibition against both VACV and MPXV.
  • MMF targets a post-entry stage in the viral replication cycle.
  • MMF suppresses USP5-mediated deubiquitination of IMPDH2, induces R&R assembly, reduces dNTP pools, and enhances antiviral effects.

Conclusions:

  • MMF is an effective antiviral drug against VACV and MPXV infections.
  • This study establishes a host-directed therapeutic strategy for orthopoxvirus infections.
  • MMF represents a potential novel therapeutic for combating future orthopoxvirus outbreaks.
Keywords:
IMPDH2Monkeypox virus (MPXV)Mycophenolate mofetil (MMF)Rod/ring structuresUbiquitin-specific protease 5 (USP5)Vaccinia virus

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