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Vet Microbiol. 2018 Feb;214:125-131. doi: 10.1016/j.vetmic.2017.12.016. Epub 2017 Dec 27.

Broad anti-herpesviral activity of α-hydroxytropolones.

Author information

1
Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States.
2
Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, PhD Program in Chemistry, The Graduate Center, The City University of New York, New York, NY, United States.
3
Department of Molecular Microbiology & Immunology, Saint Louis University School of Medicine,St. Louis, MO, United States.
4
Center for Cancer Research, National Cancer Institute, Frederick, MD, United States.
5
Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States. Electronic address: jbaines@lsu.edu.

Abstract

Herpesviruses are ubiquitous in animals and cause economic losses concomitant with many diseases. Most of the domestic animal herpesviruses are within the subfamily Alphaherpesvirinae, which includes human herpes simplex virus 1 (HSV-1). Suppression of HSV-1 replication has been reported with α-hydroxytropolones (αHTs), aromatic ring compounds that have broad bioactivity due to potent chelating activity. It is postulated that αHTs inhibit enzymes within the nucleotidyltransferase superfamily (NTS). These enzymes require divalent cations for nucleic acid cleavage activity. Potential targets include the nuclease component of the herpesvirus terminase (pUL15C), a highly conserved NTS-like enzyme that cleaves viral DNA into genomic lengths prior to packaging into capsids. Inhibition of pUL15C activity in biochemical assays by various αHTs previously revealed a spectrum of potencies. Interestingly, the most potent anti-pUL15C αHT inhibited HSV-1 replication to a limited extent in cell culture. The aim of this study was to evaluate three different αHT molecules with varying biochemical anti-pUL15C activity for a capacity to inhibit replication of veterinary herpesviruses (BoHV-1, EHV-1, and FHV-1) and HSV-1. Given the known discordant potencies between anti-pUL15C and HSV-1 replication inhibition, a second objective was to elucidate the mechanism of action of these compounds. The results show that αHTs broadly inhibit herpesviruses, with similar inhibitory effect against HSV-1, BoHV-1, EHV-1, and FHV-1. Based on immunoblotting, Southern blotting, and real-time qPCR, the compounds were found to specifically inhibit viral DNA replication. Thus, αHTs represent a new class of broadly active anti-herpesviral compounds with potential veterinary applications.

KEYWORDS:

Anti-herpesvirus; Herpesvirus; Nucleotidyltransferase superfamily; α-hydroxytropolones

PMID:
29408023
PMCID:
PMC6292515
DOI:
10.1016/j.vetmic.2017.12.016
[Indexed for MEDLINE]
Free PMC Article

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