Oligonucleotides as antivirals: Dream or realistic perspective?

Van Aerschot, Arthur

doi:10.1016/j.antiviral.2006.03.003

Cited by 26 publications

(19 citation statements)

References 67 publications

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“…In addition, the currently used antivirals cannot prevent reactivation of latent HCMV infection or the expression of IE proteins which play crucial roles in viral pathogenesis and immunomodulation. The importance of IE functions and the inability of currently available antiviral therapies to prevent their expression have led to the suggestion that prevention of their expression and/or functions may provide an alternative strategy to inhibit HCMV reactivation, replication, and immunopathogenesis (25,33). What is needed, therefore, is the identification of novel anticytomegaloviral agents that can block either HCMV entry and/or gene expression at very early stages, without causing major adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Phosphorothioate-Modified Oligodeoxynucleotides Inhibit Human Cytomegalovirus Replication by Blocking Virus Entry

Luganini

Caposio

Landolfo

et al. 2008

Antimicrob Agents Chemother

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Studies in animal models have provided evidence that Toll-like receptor 9 (TLR9) agonists, such as synthetic oligodeoxynucleotides (ODNs) that contain immunostimulatory deoxycytidyl-deoxyguanosine (CpG) motifs (CpG ODNs), protect against a wide range of viral pathogens. This antiviral activity has been suggested to be indirect and secondary to CpG-induced cytokines and inflammatory responses triggered through TLR9 activation. However, few studies have addressed the potential of CpG ODNs as direct antiviral agents. Here, we report on the ability of some CpG ODNs to directly suppress, almost completely, human cytomegalovirus (HCMV) replication in both primary fibroblasts and endothelial cells. Murine CMV replication was inhibited as well, whereas no inhibition was observed for herpes simplex virus type 1, adenovirus, or vesicular stomatitis virus. The antiviral activity of these ODNs was significantly reduced when they were added after virus adsorption, indicating that their action may be primarily targeted to the very early phases of the HCMV cycle. In fact, the B-class prototype CpG ODN 2006 effectively prevented the nuclear localization of pp65 and input viral DNA, which suggests that it inhibits HCMV entry. Moreover, a CpG 2006 control, ODN 2137 without CpG motifs, also showed a potent inhibitory activity on the HCMV entry phase, indicating that the anticytomegaloviral activity is independent of the CpG motif. In contrast, a phosphodiester version of CpG 2006 showed reduced antiviral activity, indicating that the inhibitory activity is dependent on the phosphorothioate backbone of the ODN. These results suggest that this yet-unrecognized activity of CpG ODNs may be of interest in the development of novel anticytomegaloviral molecules.

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Section: Discussionmentioning

confidence: 99%

Phosphorothioate-Modified Oligodeoxynucleotides Inhibit Human Cytomegalovirus Replication by Blocking Virus Entry

Luganini

Caposio

Landolfo

et al. 2008

Antimicrob Agents Chemother

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“…This means that phosphatemethylated DNA is in fact unsuitable as a selective agent for the inhibition of the above-mentioned HIV-1 RNA loops. [12][13][14] It should be mentioned that a number of research groups have tried to synthesize long fragments of phosphatemethylated DNA involving solid supports. This procedure was used by Kuijpers et al for the synthesis of welldefined phosphatemethylated DNA fragment, [20] and by Alul et al for the synthesis of sensitive oligonucleotide derivatives.…”

Section: Phosphatemethylated Dnamentioning

confidence: 99%

“…In a review article of 2006, van Aerschot [12] describes the beginnings and current status of the antisense domain. In this paper, he also focuses the attention on a retracted paper in Science of 1990 by Buck et al, based on the inhibition of phosphatemethylated DNA aimed at HIV-1 RNA loops and integrated DNA.…”

Section: Phosphatemethylated Dnamentioning

confidence: 99%

Dna Systems for B-Z Transition and Their Significance as Epigenetic Model: The Fundamental Role of the Methyl Group

Buck¹

2011

Nucleosides, Nucleotides and Nucleic Acids

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Epigenetic systems involved in the dynamics of gene expression, which are fundamental to cell determination and function without alteration in DNA sequences, are based on methylation of the N-terminal tails of lysine residues and DNA methylation. We demonstrate the vital importance for genetic transfer by different (hydrogen) networks, suggesting a complex interaction between the two epigenetic modifications. In other words, the methylation of local lysines can prescribe C(P)G methylation, which requires that methylation of histones and DNA are cooperative in carrying out an epigenetic instruction for integrating gene-silencing networks. To give a bio-organic description of the epigenetic coherence between histone and base methylation, we used the well-known B- into Z-DNA dynamics in combination with the unique properties of phosphatemethylated DNA on different levels of chemistry.

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“…The pioneering work of Zamecnik and Stephenson (1978), who developed an antisense oligonucleotide as a potential therapy, aimed to inhibit viral growth and replication by targeting the reiterated 3 0 -and 5 0 -terminal nucleotides of Rous sarcoma virus 35S RNA. Reports focused on inhibition of viral targets multiplied quickly due to the large number of potential viral pathogens times the number of potential targets within each pathogen (Van Aerschot, 2006). Limitations of antisense as pathogen-targeted antibiotics include cost, narrow spectrum of activity, challenge for enhancing delivery, and uptake by pathogens at site of infection in a safe manner (Bennett and Swayze, 2010).…”

Section: Discussionmentioning

confidence: 99%

Targeting Host E-Selectin Expression by Antisense Oligodeoxynucleotides as Potential Antiendotoxin TherapyIn Vivo

et al. 2010

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This study sought to determine if antisense oligodeoxynucleotides would inhibit E-selectin expression, which mediates leukocyte adhesion on endothelial cells, otherwise induced by in vivo endotoxin challenge. Six antisense phosphorothioate oligodeoxynucleotides calculated to bind porcine E-selectin mRNA were tested in porcine aortic endothelial cells. One, ISIS9481, exerted significant inhibition of E-selectin expression induced by tumor necrosis factor-α + endotoxin [lipopolysaccharide (LPS)]. Pigs were challenged with LPS (10 μg/kg) and treated with ISIS9481 (10 mg/kg) (n = 6). Two control groups were used, an antisense inactive in porcine aortic endothelial cells (n = 6) and saline (n = 5), and were combined as control (C = 11). Control pigs challenged with LPS expressed E-selectin in heart, lung, kidneys, and liver, whereas antisense-treated pigs expressed little E-selectin in these tissues. Cardiovascular data indicated that antisense treatment attenuated pathophysiological alterations induced by LPS. Specifically, in control pigs, LPS reduced cardiac output 32% from baseline, increased pulmonary (+116%) and systemic vascular resistances (+16%), and generated neutropenia (from 51,000 at basal to 18,000 polymorphonuclear neutrophils (PMN)/μL after LPS). In antisense-treated pigs, cardiac output decreased only 18%, pulmonary vascular resistance remained unchanged, whereas systemic vascular resistance decreased compared with basal values (-37%). PMN counts remained at 45,000-54,000/μL at 3-4 hours after LPS. These data demonstrate that antisense oligodeoxynucleotides, designed and tested in vitro to interact with 1 gene product, can be developed as either therapeutics or experimental tools in vivo.

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Oligonucleotides as antivirals: Dream or realistic perspective?

Cited by 26 publications

References 67 publications

Phosphorothioate-Modified Oligodeoxynucleotides Inhibit Human Cytomegalovirus Replication by Blocking Virus Entry

Phosphorothioate-Modified Oligodeoxynucleotides Inhibit Human Cytomegalovirus Replication by Blocking Virus Entry

Dna Systems for B-Z Transition and Their Significance as Epigenetic Model: The Fundamental Role of the Methyl Group

Targeting Host E-Selectin Expression by Antisense Oligodeoxynucleotides as Potential Antiendotoxin TherapyIn Vivo

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