Identifier

etd-04102017-104545

Degree

Master of Science (MS)

Department

Veterinary Medical Sciences - Pathobiological Sciences

Document Type

Thesis

Abstract

Herpesviruses are ubiquitous in animals and cause economic losses concomitant with many diseases, including upper respiratory disease, keratitis, abortion, neonatal death, and neurologic disease. The majority of the domestic animal herpesviruses are within the subfamily Alphaherpesvirinae, along with the prototypical human herpes simplex virus 1 (HSV-1). Suppression of HSV-1 replication has been reported with α-hydroxytropolones (αHTs), which are aromatic ring compounds that have broad bioactivity due to potent chelating activity. It is postulated that αHTs inhibit enzymes within the nucleotidyltransferase superfamily (NTS), similarly structured enzymes that require divalent cations for nucleic acid cleavage activity. One potential herpesviral target includes the nuclease of the viral terminase, a highly conserved NTS-like enzyme that cleaves the viral genome for packaging into capsids. Inhibition of the nuclease activity of the viral terminase (pUL15C) by αHTs previously revealed variable potencies, ranging from negligible to marked. Interestingly, the most potent anti-terminase nuclease αHT compounds had limited effect on inhibiting HSV-1 replication. The aim of this study was to evaluate three different αHT molecules with varying in vitro anti-terminase nuclease activity against veterinary herpesviruses (BoHV-1, EHV-1, FHV-1) and HSV-1 to assess for broad inhibitory activity. Additionally, given the discordant potencies between anti-pUL15C and HSV-1 inhibition, a second objective was to elucidate the mechanism of action of these compounds. The results of this research show that αHTs broadly inhibit herpesviruses, with similar inhibitory effect among HSV-1, BoHV-1, EHV-1, and FHV-1 with IC50 values ranging from 30 to ≤ 5 μM. Based on immunoblotting, Southern blotting, and real-time qPCR, the compounds were found to specifically inhibit DNA replication. Thus, αHTs may represent a new class of anti-herpesviral compounds.

Date

2017

Document Availability at the Time of Submission

Secure the entire work for patent and/or proprietary purposes for a period of one year. Student has submitted appropriate documentation which states: During this period the copyright owner also agrees not to exercise her/his ownership rights, including public use in works, without prior authorization from LSU. At the end of the one year period, either we or LSU may request an automatic extension for one additional year. At the end of the one year secure period (or its extension, if such is requested), the work will be released for access worldwide.

Committee Chair

Baines, Joel

Available for download on Saturday, February 23, 2019

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