Current and Potential Treatments for Ubiquitous but Neglected Herpesvirus Infections

Gable, Jonathan E.; Acker, Timothy M.; Craik, Charles S.

doi:10.1021/cr500255e

Cited by 25 publications

(32 citation statements)

References 313 publications

(409 reference statements)

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“…For example, clinical trials assessing the efficacy of oral and ophthalmologic anti-FHV-1 therapy in cats with FHV-1 revealed improved clinical signs with limited adverse effects (Fontenelle et al, 2008; Gould, 2011; Thomasy et al, 2011; Thomasy et al, 2016). In people, most anti-herpesviral therapeutics target the viral DNA polymerase, in which acquired mutations and subsequent viral resistance are a major limitation, especially in patients undergoing prolonged therapy (Collins and Darby, 1991; Gable et al, 2014; Krawczyk et al, 2013). Thus, a great need exists for novel anti-herpesviral compounds in both medical and veterinary medicine.…”

Section: Introductionmentioning

confidence: 99%

Broad anti-herpesviral activity of α-hydroxytropolones

Dehghanpir

Birkenheuer

Yang

et al. 2018

Veterinary Microbiology

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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.

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Section: Introductionmentioning

confidence: 99%

Broad anti-herpesviral activity of α-hydroxytropolones

Dehghanpir

Birkenheuer

Yang

et al. 2018

Veterinary Microbiology

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“…Small molecules that target the portal or terminase proteins of the DNA cleavage and packag- ing machinery of herpesviruses have been described (1,39,(56)(57)(58)(59)(60)(61)(62)(63). Several small-molecule compounds have been identified that specifically target HCMV pUL56 (the pORF30 homolog).…”

Section: Discussionmentioning

confidence: 99%

Intermolecular Complementation between Two Varicella-Zoster Virus pORF30 Terminase Domains Essential for DNA Encapsidation

Visalli

House

Lahrman

et al. 2015

J Virol

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The herpesviral terminase complex is part of the intricate machinery that delivers a single viral genome into empty preformed capsids (encapsidation). The varicella-zoster virus (VZV) terminase components (pORF25, pORF30, and pORF45/42) have not been studied as extensively as those of herpes simplex virus 1 and human cytomegalovirus (HCMV). In this study, VZV bacterial artificial chromosomes (BACs) were generated with small (⌬30S), medium (⌬30M), and large (⌬30L) ORF30 internal deletions. In addition, we isolated recombinant viruses with specific alanine substitutions in the putative zinc finger motif (30-ZF3A) or in a conserved region (region IX) with predicted structural similarity to the human topoisomerase I core subdomains I and II ( During herpesvirus replication, large head-to-tail doublestranded DNA (dsDNA) concatemers accumulate in the infected-cell nucleus and are subsequently packaged into preformed viral capsids. The packaging process is complex and involves a group of proteins that recognize specific viral DNA sequences and simultaneously process and translocate unit-length genomes through the portal vertex of the procapsid (1). The protein complex that docks or interacts with the capsid portal protein consists of the heterotrimeric viral terminase. Terminases of DNA bacteriophages have been well described (2, 3), and those of several members of the Herpesviridae, including herpes simplex virus 1 (HSV-1) (4-14), human cytomegalovirus (HCMV) (15-21), Epstein-Barr virus (EBV) (22), and varicella-zoster virus (VZV) (23)(24)(25), are under investigation.Members of the Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae share a core set of orthologous proteins required for DNA encapsidation. A heterotrimeric viral terminase complex consisting of three of these conserved core proteins was recently isolated from HSV-1-infected cells (4). The HSV-1 terminase consisted of a 1:1:1 equimolar complex of two different terminase protein subunits, pUL15 and pUL28, and a protein encoded by the UL33 gene family. The pUL33 component may act as an essential accessory protein involved in the formation and/or stability of the terminase complex (7). Homologous terminase components have also been identified for HCMV (pUL89, pUL56, and pUL51) (16)(17)(18)(19)(20)(21)(26)(27)(28) and VZV (pORF45/42, pORF30, and

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“…The history and potential of this compound and closely related compounds have recently been published and these papers should be consulted by interested readers. [40][41][42][43][44] It should also be mentioned that significant numbers of antiviral drugs against HIV are now delivered as preadjusted combinations of reverse transcriptase, integrase and protease inhibitors, which have the potential to reduce this disease to chronic status. An example uses emtricitabine (84) and tenofovir (82) plus the non-nucleoside reverse transcriptase inhibitor (rilpivirine; structure not shown as not a nucleoside …”

Section: Antiviral Agents Based On Nucleosidesmentioning

confidence: 99%

Natural Product-Derived Drugs Based on β-Adrenergic Agents and Nucleosides

Newman¹

2016

Journal of the Brazilian Chemical Society

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This relatively short review demonstrates the very important role of the structures of the natural products adrenaline and relatives, in the design and subsequent approval of β-agonists and antagonists, and of modified nucleosides as anticancer, and in particular, antiviral agents against herpes (HSV), human immunodeficiency virus (HIV) and hepatitis C virus (HCV) that would not have been synthesized in the absence of knowledge of bioactive arabinose nucleosides.

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Current and Potential Treatments for Ubiquitous but Neglected Herpesvirus Infections

Cited by 25 publications

References 313 publications

Broad anti-herpesviral activity of α-hydroxytropolones

Broad anti-herpesviral activity of α-hydroxytropolones

Intermolecular Complementation between Two Varicella-Zoster Virus pORF30 Terminase Domains Essential for DNA Encapsidation

Natural Product-Derived Drugs Based on β-Adrenergic Agents and Nucleosides

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