Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function

Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3609-14. doi: 10.1073/pnas.1523686113. Epub 2016 Mar 14.

Abstract

Clinically available drugs active against Epstein-Barr virus (EBV) and other human herpesviruses are limited to those targeting viral DNA replication. To identify compounds directed against other steps in the viral life cycle, we searched for drugs active against the EBV SM protein, which is essential for infectious virus production. SM has a highly gene-specific mode of action and preferentially enhances expression of several late lytic cycle EBV genes. Here we demonstrate that spironolactone, a mineralocorticoid receptor antagonist approved for clinical use, inhibits SM function and infectious EBV production. Expression of EBV viral capsid antigen is highly SM dependent, and spironolactone inhibits viral capsid antigen synthesis and capsid formation, blocking EBV virion production at a step subsequent to viral DNA replication. In addition, spironolactone inhibits expression of other SM-dependent genes necessary for infectious virion formation. We further demonstrate that molecules structurally related to spironolactone with similar antimineralocorticoid blocking activity do not inhibit EBV production. These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action directed against SM and homologous essential proteins in other herpesviruses.

Keywords: Epstein–Barr virus; antiviral; herpesvirus; posttranscriptional regulation; spironolactone.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antiviral Agents / pharmacology*
  • Capsid Proteins / antagonists & inhibitors
  • Capsid Proteins / genetics
  • Capsid Proteins / physiology
  • Cell Line
  • DNA Replication / drug effects
  • Gene Deletion
  • Gene Expression Regulation, Viral / drug effects
  • Gene Knockout Techniques
  • Genes, Viral / drug effects
  • HEK293 Cells
  • Herpesvirus 4, Human / drug effects*
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / physiology*
  • Humans
  • Immediate-Early Proteins / antagonists & inhibitors*
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / physiology
  • Mineralocorticoid Receptor Antagonists / pharmacology
  • Spironolactone / analogs & derivatives
  • Spironolactone / chemistry
  • Spironolactone / pharmacology*
  • Structure-Activity Relationship
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / genetics
  • Trans-Activators / physiology
  • Transcriptome / drug effects
  • Virus Release / drug effects
  • Virus Replication / drug effects
  • Virus Replication / genetics
  • Virus Replication / physiology

Substances

  • Antiviral Agents
  • BRLF1 protein, Human herpesvirus 4
  • Capsid Proteins
  • Immediate-Early Proteins
  • Mineralocorticoid Receptor Antagonists
  • Trans-Activators
  • Spironolactone