title: Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function.
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.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Verma
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132.
authors.forename: Jacob
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132 sankar.swaminathan@hsc.utah.edu.
authors.forename: Sankar
authors.initials: S
authors.lastname: Swaminathan
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D036022:Capsid Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D017353:Gene Deletion; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D055786:Gene Knockout Techniques; D005814:Genes, Viral / Q000187:drug effects; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D013148:Spironolactone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D059467:Transcriptome / Q000187:drug effects; D057074:Virus Release / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D000998:Antiviral Agents; C068382:BRLF1 protein, Human herpesvirus 4; D036022:Capsid Proteins; D017874:Immediate-Early Proteins; D000451:Mineralocorticoid Receptor Antagonists; D015534:Trans-Activators; D013148:Spironolactone
keywords: Epstein–Barr virus; antiviral; herpesvirus; posttranscriptional regulation; spironolactone