UL52 Primase Interactions in the Herpes Simplex Virus 1 Helicase-Primase Are Affected by Antiviral Compounds and Mutations Causing Drug Resistance

Muylaert, Isabella; Zhao, Zhiyuan; Elias, Per

doi:10.1074/jbc.m114.609453

Cited by 11 publications

(16 citation statements)

References 31 publications

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“…Thus, the putative antigenic determinants of glycoprotein B and major capsid protein might be potential targets for epitope-based vaccine development for protective immune response against infections caused by HHVs. Although no antigenic determinant is located in helicase enzyme of HHVs, the complex of this enzyme with primase is suggested to be an efficient drug target against the infections caused by HSV-1 [ 27 ], HSV-2 [ 28 ], and HHV-3 [ 29 ]. Thus, helicase and putative antigenic determinants of glycoprotein B and major capsid protein of HHVs may become effective targets for drug and vaccine development; experimental investigations are required to develop therapeutics and drugs using these targets.…”

Section: Resultsmentioning

confidence: 99%

Comparative Genomics of Herpesviridae Family to Look for Potential Signatures of Human Infecting Strains

Sharma

Mobeen

Prakash

2016

International Journal of Genomics

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Herpesviridae family is one of the significant viral families which comprises major pathogens of a wide range of hosts. This family includes at least eight species of viruses which are known to infect humans. This family has evolved 180–220 million years ago and the present study highlights that it is still evolving and more genes can be added to the repertoire of this family. In addition, its core-genome includes important viral proteins including glycoprotein B and helicase. Most of the infections caused by human herpesviruses have no definitive cure; thus, search for new therapeutic strategies is necessary. The present study finds core-genome of human herpesviruses that differs from that of Herpesviridae family and nonhuman herpes strains of this family and might be a putative target for vaccine development. The phylogenetic reconstruction based upon the protein sequences of core gene set of Herpesviridae family reveals the sharp splits of its different subfamilies and supports the hypothesis of coevolution of viruses with their hosts. In addition, data mining for cis-elements in the genomes of human herpesviruses results in the prediction of numerous regulatory elements which can be used for regulating the expression of viral based vectors implicated in gene therapies.

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Section: Resultsmentioning

confidence: 99%

Comparative Genomics of Herpesviridae Family to Look for Potential Signatures of Human Infecting Strains

Sharma

Mobeen

Prakash

2016

International Journal of Genomics

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“…However, unlike HSVprotein targeting helicase-primase inhibitors, peg-ArgI modulation of host arginine-associated metabolic pathways minimizes the likelihood that viruses could evolve resistance. This would contrast virus-targeted nucleoside analogs and helicase-primase inhibitors where mutations that confer resistance are easily identified (Biswas et al, 2007; Coen and Schaffer, 1980; Fleming and Coen, 1984; Muylaert et al, 2014; Pelosi et al, 1998). …”

Section: Discussionmentioning

confidence: 99%

Development and evaluation of a host-targeted antiviral that abrogates herpes simplex virus replication through modulation of arginine-associated metabolic pathways

2016

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Since their inception five decades ago, most antivirals have been engineered to disrupt a single viral protein or process that is essential for viral replication. This approach has limited the overall therapeutic effectiveness and applicability of current antivirals due to restricted viral specificity, a propensity for development of drug resistance, and an inability to control deleterious host-mediated inflammation. As obligate intracellular parasites, viruses are reliant on host metabolism and macromolecular synthesis pathways. Of these biosynthetic processes, many viruses, including Herpes simplex viruses (HSV), are absolutely dependent on the bioavailability of arginine, a non-essential amino acid that is critical for many physiological and pathophysiological processes associated with either facilitating viral replication or progression of disease. To assess if targeting host arginine-associated metabolic pathways would inhibit HSV replication, a pegylated recombinant human Arginase I (peg-ArgI) was generated and its in vitro anti-herpetic activity was evaluated. Cells continuously treated with peg-ArgI for over 48 hours exhibited no signs of cytotoxicity or loss of cell viability. The antiviral activity of peg-ArgI displayed a classical dose-response curve with IC50’s in the sub-nanomolar range. peg-ArgI potently inhibited HSV-1 and HSV-2 viral replication, infectious virus production, cell-to-cell spread/transmission and virus-mediated cytopathic effects. Not unexpectedly given its host-targeted mechanism of action, peg-ArgI showed similar effectiveness at controlling replication of single and multidrug resistant HSV-1 mutants. These findings illustrate that targeting host arginine-associated metabolic pathways is an effective means of controlling viral replicative processes. Further exploration into the breadth of viruses inhibited by peg-ArgI, as well as the ability of peg-ArgI to suppress arginine-associated virus-mediated pathophysiological disease processes is warranted.

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“…ICP8 presumably stimulates synthesis on the leading strand by preventing reannealing of ssDNA unwound by UL5/UL8/UL52. In addition, the direct interaction between ICP8, UL8, and UL52 has been reported recently (19). The collaboration of ICP8 with the subunits of the helicase/primase might be required for the coupled synthesis.…”

Section: Discussionmentioning

confidence: 94%

DNA Replication Catalyzed by Herpes Simplex Virus Type 1 Proteins Reveals Trombone Loops at the Fork*

Bermek

Willcox

Griffith

2015

Journal of Biological Chemistry

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UL52 Primase Interactions in the Herpes Simplex Virus 1 Helicase-Primase Are Affected by Antiviral Compounds and Mutations Causing Drug Resistance

Cited by 11 publications

References 31 publications

Comparative Genomics of Herpesviridae Family to Look for Potential Signatures of Human Infecting Strains

Comparative Genomics of Herpesviridae Family to Look for Potential Signatures of Human Infecting Strains

Development and evaluation of a host-targeted antiviral that abrogates herpes simplex virus replication through modulation of arginine-associated metabolic pathways

DNA Replication Catalyzed by Herpes Simplex Virus Type 1 Proteins Reveals Trombone Loops at the Fork*

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