Inhibition of herpes simplex virus in culture by oligonucleotides composed entirely of deoxyguanosine and thymidine

Fennewald, Susan M.; Mustain, Shawn D.; Ojwang, Joshua O.; Rando, Robert F.

doi:10.1016/0166-3542(94)00064-f

Cited by 26 publications

(18 citation statements)

References 28 publications

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“…Although much recent attention has focused on small interfering RNAs, the majority of oligonucleotides that have been studied as antiviral agents to date are modified oligodeoxynucleotides (ODNs) designed to work via an antisense mechanism, such as the licensed anticytomegalovirus drug, fomivirsen (2,3). However, other ODNs with antiviral activity are not complementary to viral nucleic acid (13,31,35). These ODNs are GT rich and have the propensity to form G-quartet structures stabilized by non-Watson-Crick guanineguanine base pairs (reviewed in references 26 and 33).…”

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Virucidal Activity of a GT-Rich Oligonucleotide against Herpes Simplex Virus Mediated by Glycoprotein B

Shogan

Kruse

Mulamba

et al. 2006

J Virol

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We have investigated the antiviral mechanism of a phosphorothioate oligonucleotide, ISIS 5652, which has activity against herpes simplex virus (HSV) in the low micromolar range in plaque reduction assays. We isolated a mutant that is resistant to this compound. Marker rescue and sequencing experiments showed that resistance was due to at least one of three mutations in the UL27 gene which result in amino acid changes in glycoprotein B (gB). Because gB has a role in attachment and entry of HSV, we tested the effects of ISIS 5652 at these stages of infection. The oligonucleotide potently inhibited attachment of virus to cells at 4°C; however, the resistant mutant did not exhibit resistance at this stage. Moreover, a different oligonucleotide with little activity in plaque reduction assays was as potent as ISIS 5652 in inhibiting attachment. Similarly, ISIS 5652 was able to inhibit entry of preattached virions into cells at 37°C, but the mutant did not exhibit resistance in this assay. The mutant did not attach to or enter cells more quickly than did wild-type virus. Strikingly, incubation of wild-type virus with 1 to 2 M ISIS 5652 at 37°C led to a time-dependent, irreversible loss of infectivity (virucidal activity). No virucidal activity was detected at 4°C or with an unrelated oligonucleotide at 37°C. The resistant mutant and a marker-rescued derivative containing its gB mutations exhibited substantial resistance to this virucidal activity of ISIS 5652. We hypothesize that the GT-rich oligonucleotide induces a conformational change in gB that results in inactivation of infectivity.Oligonucleotides hold considerable promise for treating viral infections. Although much recent attention has focused on small interfering RNAs, the majority of oligonucleotides that have been studied as antiviral agents to date are modified oligodeoxynucleotides (ODNs) designed to work via an antisense mechanism, such as the licensed anticytomegalovirus drug, fomivirsen (2, 3). However, other ODNs with antiviral activity are not complementary to viral nucleic acid (13,31,35). These ODNs are GT rich and have the propensity to form G-quartet structures stabilized by non-Watson-Crick guanineguanine base pairs (reviewed in references 26 and 33). Certain of these GT-rich ODNs have anti-human immunodeficiency virus (HIV) activity and, evidently, target the HIV envelope protein gp120 (12,35). Others have been reported to exhibit activity against herpes simplex virus (HSV), but their mechanism(s) of action are not known (13).HSV most commonly causes genital herpes, cold sores, and corneal keratitis and can cause more severe disease, particularly in the immunocompromised (reviewed in reference 32). The virion consists of an icosahedral nucleocapsid containing the ϳ150-kbp double-stranded DNA genome, surrounded by a less-ordered layer of proteins called the tegument and a lipid bilayer envelope that contains a number of virus-encoded glycoproteins (reviewed in reference 25). The replication cycle of HSV begins with the initial attachment of viru...

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confidence: 99%

Virucidal Activity of a GT-Rich Oligonucleotide against Herpes Simplex Virus Mediated by Glycoprotein B

Shogan

Kruse

Mulamba

et al. 2006

J Virol

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“…The action of oligonucleotides against herpes simplex virus and human cytomegalovirus have been reported previously (3,8,9), but the actual analysis of the data has been complicated by the ability of the oligonucleotides to operate on the exterior of the cell as inhibitors of viral adsorption. The binding of herpes simplex virus to the cell involves an initial attachment to cell surface heparan sulfate molecules and can be competed by the addition of heparin to the media (21).…”

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“…Our own studies progressed from the initial use of oligonucleotides as anti-herpesvirus agents on Vero and MRC-5 cells (9). The action of oligonucleotides against herpes simplex virus and human cytomegalovirus have been reported previously (3,8,9), but the actual analysis of the data has been complicated by the ability of the oligonucleotides to operate on the exterior of the cell as inhibitors of viral adsorption.…”

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confidence: 99%

“…Compounds are most often designed as antisense agents and, as such, have shown efficacy in cell culture and in some animal models of disease. Efficacious oligonucleotides have been used against viruses, including human cytomegalovirus, herpes simplex virus, human immunodeficiency virus, and papillomavirus, and against various cellular targets, including the oncogenes c-myc, c-myb, and c-abl (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). In addition investigators have used anti-cmyc/-myb antisense oligonucleotides to prevent restenosis in animal models (13)(14)(15).…”

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“…The binding of herpes simplex virus to the cell involves an initial attachment to cell surface heparan sulfate molecules and can be competed by the addition of heparin to the media (21). Phosphorothioate oligonucleotides are particularly potent inhibitors of viral adsorption with effective concentrations in the nanomolar range (9,22). Because basic fibroblast growth factor (bFGF) binding, like herpes simplex virus adsorption, involves interaction with cell surface heparan sulfate, we investigated whether oligonucleotides would also inhibit the binding of bFGF to cells.…”

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Inhibition of High Affinity Basic Fibroblast Growth Factor Binding by Oligonucleotides

Fennewald

Rando

1995

Journal of Biological Chemistry

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Oligonucleotides can be used to inhibit the binding of basic fibroblast growth factor to cells. Though standard phosphodiester oligonucleotides show a slight inhibition of binding, the oligonucleotides with phosphorothioate internucleoside linkages have inhibition levels equivalent to that of the polyanion heparin. Variations in sequence of the oligonucleotides does lead to differences in the inhibitory action of the oligonucleotides. This inhibition of basic fibroblast growth factor by phosphorothioate oligonucleotides may account for much of the published data on inhibition of various genes by proposed antisense oligonucleotides and needs to be taken into account when considering the mechanism of action of oligonucleotides in biological systems.

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A Hitchhiker's guide to antisense and nonantisense biochemical pathways

Branch

1996

Hepatology

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Antisense pharmaceutical research has sought to provide drugs that would yield effective therapies for disAntisense pharmaceutical research has sought to strategieases resulting from the production of deleterious pro-cally design drugs that would predictably yield safe and effecteins. The original concept was straightforward: tive therapies. It is now clear that a broad knowledge of nueliminate production of unwanted proteins, such as on-cleic acid biochemistry will be needed to attain this goal and cogenic proteins, by blocking the function of their other related objectives. As originally conceived, antisense mRNAs; and block their mRNAs by adding ''antisense'' strategies were to offer a general and rational approach for nucleic acids that bind them through complementary designing treatments for all diseases resulting from the probase pairing. However, it has proven difficult to develop duction of deleterious proteins, such as viral, oncogenic, cytoclinically useful antisense strategies. Conventional anti-toxic, misfolded, or overly abundant proteins (including pepsense nucleic acids are large, highly charged, complex tide hormones). Figure 1 illustrates one type of antisense molecules that interact with a wide variety of unin-approach. In this model, the therapeutic molecule is an antitended cellular and microbial components, often caus-sense DNA oligonucleotide. It is composed of sequences coming ''nonantisense effects.'' It is now clear that a broad plementary to its target, a messenger (mRNA). The mRNA knowledge of nucleic acid biochemistry will be needed contains genetic information in the functional, or sense, orito optimize antisense molecules for use in patients. The entation. In the ideal strategy, binding of the antisense oligoefficacy of naturally occurring antisense molecules and nucleotide inactivates the intended mRNA and prevents its the success of antisense agricultural strategies prove translation into protein, while leaving all other RNAs unafthat antisense approaches can be powerful and specific. fected.5 Antisense strategies are based on biochemical experiPharmaceutical antisense research can be expected to ments showing 1) that proteins are translated from specific yield many valuable products once sufficient informa-RNAs; 2) that once the sequence of an RNA is known, it is tion about antisense mechanisms has been gathered and possible to design an antisense molecule that will bind to it applied. This article explains the biochemical events through complementary Watson-Crick base pairs; and 3) that that give rise to both antisense and nonantisense effects by manipulating conditions in vitro, it is possible to obtain and provides guidelines for designing and evaluating sequence-specific binding, albeit under conditions that are antisense experiments. (HEPATOLOGY 1996;24:1517-1529.) often far outside the physiological range.Several factors make it difficult to develop clinical applications of the classical antisense model presented in Fig. 1. PREAMBLEFirst, conventional antisense nucleic acid...

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Inhibition of herpes simplex virus in culture by oligonucleotides composed entirely of deoxyguanosine and thymidine

Cited by 26 publications

References 28 publications

Virucidal Activity of a GT-Rich Oligonucleotide against Herpes Simplex Virus Mediated by Glycoprotein B

Virucidal Activity of a GT-Rich Oligonucleotide against Herpes Simplex Virus Mediated by Glycoprotein B

Inhibition of High Affinity Basic Fibroblast Growth Factor Binding by Oligonucleotides

A Hitchhiker's guide to antisense and nonantisense biochemical pathways

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