title: Zinc ionophores pyrithione inhibits herpes simplex virus replication through interfering with proteasome function and NF-κB activation.
abstract: Pyrithione (PT), known as a zinc ionophore, is effective against several pathogens from the Streptococcus and Staphylococcus genera. The antiviral activity of PT was also reported against a number of RNA viruses. In this paper, we showed that PT could effectively inhibit herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). PT inhibited HSV late gene (Glycoprotein D, gD) expression and the production of viral progeny, and this action was dependent on Zn(2+). Further studies showed that PT suppressed the expression of HSV immediate early (IE) gene, the infected cell polypeptide 4 (ICP4), but had less effect on another regulatory IE protein, ICP0. It was found that PT treatment could interfere with cellular ubiquitin-proteasome system (UPS), leading to the inhibition of HSV-2-induced IκB-α degradation to inhibit NF-κB activation and enhanced promyelocytic leukemia protein (PML) stability in nucleus. However, PT did not show direct inhibition of 26S proteasome activity. Instead, it induced Zn(2+) influx, which facilitated the dysregulation of UPS and the accumulation of intracellular ubiquitin-conjugates. UPS inhibition by PT caused disruption of IκB-α degradation and NF-κB activation thus leading to marked reduction of viral titer.
authors.affiliation: Center for Public Health Research, Medical School, Nanjing University, Nanjing, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Qiu
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Chu
authors.forename: Siwei
authors.initials: S
authors.lastname: Song
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D006561:Herpes Simplex / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D007476:Ionophores / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D013871:Thiones / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D007476:Ionophores; D016328:NF-kappa B; D011725:Pyridines; D013871:Thiones; C008704:pyrithione; D046988:Proteasome Endopeptidase Complex; D015032:Zinc
keywords: Antiviral activity; Herpes simplex virus; NF-κB; Pyrithione (PT); Ubiquitin-proteasome system (UPS); Zinc ionophore