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Zinc ionophores pyrithione inhibits herpes simplex virus replication through interfering with proteasome function and

Min Qiu1, Yu Chen, Ying Chu

  • 1Center for Public Health Research, Medical School, Nanjing University, Nanjing, PR China.

Antiviral Research
|July 23, 2013
PubMed

Insights

Pyrithione (PT) effectively inhibits herpes simplex viruses (HSV-1 and HSV-2) by disrupting the ubiquitin-proteasome system (UPS). This zinc-dependent antiviral action reduces viral gene expression and progeny production.

Area of Science:

  • Virology
  • Molecular Biology
  • Biochemistry

Background:

  • Pyrithione (PT) is a known zinc ionophore with antimicrobial and antiviral properties against RNA viruses.
  • Previous research indicates PT's efficacy against Streptococcus and Staphylococcus pathogens.
  • The antiviral mechanisms of PT, particularly against DNA viruses like HSV, require further elucidation.

Purpose of the Study:

  • To investigate the antiviral activity of Pyrithione (PT) against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2).
  • To elucidate the molecular mechanisms underlying PT's inhibitory effects on HSV replication.
  • To determine the role of zinc ions (Zn2+) and the ubiquitin-proteasome system (UPS) in PT's antiviral action.

Main Methods:

  • Cell culture and viral infection assays with HSV-1 and HSV-2.
  • Quantitative analysis of viral gene expression (late gene gD, immediate early genes ICP4 and ICP0).
  • Western blot analysis to assess protein degradation (IκB-α), activation (NF-κB), and stability (PML).
  • Assessment of 26S proteasome activity and intracellular ubiquitin-conjugate levels.
  • Measurement of intracellular zinc ion concentration.

Main Results:

  • PT significantly inhibited HSV-1 and HSV-2 replication, reducing viral progeny production.
  • PT suppressed the expression of HSV late gene Glycoprotein D (gD) and immediate early gene ICP4 in a Zn(2+)-dependent manner.
  • PT treatment interfered with the cellular ubiquitin-proteasome system (UPS), inhibiting HSV-2-induced IκB-α degradation and NF-κB activation.
  • PT enhanced the stability of promyelocytic leukemia protein (PML) in the nucleus.
  • PT did not directly inhibit 26S proteasome activity but induced Zn(2+) influx, leading to UPS dysregulation and accumulation of ubiquitin-conjugates.

Conclusions:

  • Pyrithione exhibits potent antiviral activity against HSV-1 and HSV-2.
  • The antiviral mechanism involves the disruption of the cellular ubiquitin-proteasome system (UPS) in a zinc-dependent manner.
  • PT's inhibition of viral replication is linked to the suppression of viral gene expression and modulation of host cellular pathways, including NF-κB signaling and PML stability.
Keywords:
Antiviral activityHerpes simplex virusNF-κBPyrithione (PT)Ubiquitin-proteasome system (UPS)Zinc ionophore

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