Phosphorothioate Oligodeoxynucleotides: What Is Their Origin and What Is Unique About Them?

Eckstein, Fritz

doi:10.1089/oli.1.2000.10.117

Cited by 357 publications

(225 citation statements)

References 40 publications

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“…To resolve this issue, modified PS AS-ODNs, which combine many desired pharmacokinetic properties such as high biostability, RNase H activation and target specificity, 35,36 were synthesized and administrated intravenously in vivo. PS AS-ODNs have a half-life in human serum of approximately 9-10 h as ] mice were infected intraperitoneally with CVB3 at 10 5 PFU 2 h after the first administration of AS-ODN and then followed by three additional intravenous injections at days 1, 2 and 3 p.i.…”

Section: Inhibition Of Cvb3 Replication By As-odn J Yuan Et Almentioning

confidence: 99%

A phosphorothioate antisense oligodeoxynucleotide specifically inhibits coxsackievirus B3 replication in cardiomyocytes and mouse hearts

Cheung

Zhang

Chau

et al. 2004

Laboratory Investigation

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Antisense oligodeoxynucleotides (AS-ODNs) are promising therapeutic agents for the treatment of virusinduced diseases. We previously reported that coxsackievirus B3 (CVB3) infectivity could be inhibited effectively in HeLa cells by phosphorothioate AS-ODNs complementary to different regions of the 5 0 and 3 0 untranslated regions of CVB3 RNA. The most effective target is the proximal terminus of the 3 0 untranslated region. To further investigate the potential antiviral role of the AS-ODN targeting this site in cardiomyocytes (HL-1 cell line), corresponding AS-ODN (AS-7) was transfected into the HL-1 cells and followed by CVB3 infection. Analyses by RT-PCR, Western blotting and plaque assay demonstrated that AS-7 strongly inhibits viral RNA and viral protein synthesis as compared to scrambled AS-ODNs. The percent inhibitions of viral RNA transcription and capsid protein VP1 synthesis were 87.6 and 40.1, respectively. Moreover, AS-7 could inhibit ongoing CVB3 infection when it was given after virus infection. The antiviral activity was further evaluated in a CVB3 myocarditis mouse model. Adolescent A/J mice were intravenously administrated with AS-7 or scrambled AS-ODNs prior to and after CVB3 infection. Following a 4-day therapy, the myocardium CVB3 RNA replication decreased by 68% and the viral titers decreased by 0.5 log 10 in the AS-7-treated group as compared to the group treated with the scrambled AS-ODNs as determined by RT-PCR, in situ hybridization and viral plaque assay. Taken together, our results demonstrated a great potential for AS-7 to be further developed into an effective treatment towards viral myocarditis as well as other diseases caused by CVB3 infection.

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Section: Inhibition Of Cvb3 Replication By As-odn J Yuan Et Almentioning

confidence: 99%

A phosphorothioate antisense oligodeoxynucleotide specifically inhibits coxsackievirus B3 replication in cardiomyocytes and mouse hearts

Cheung

Zhang

Chau

et al. 2004

Laboratory Investigation

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“…These issues can be overcome by chemical modifications of the phosphodiester backbone, of the purine and pyrimidine heterocyclic bases, and of the sugar moiety [3,4]. Phosphorothioate (PS)-containing oligonucleotides, where one of the nonbridging phosphate oxygen atoms is replaced by one sulfur atom, were one of the earliest and currently most widely used backbone modifications of oligonucleotide molecules [5]. Some of the desirable phosphorothioate oligonucleotide properties include binding specificity, enzymatic stability, and low toxicity.…”

Section: Introductionmentioning

confidence: 99%

A Novel and Intuitive Method of Displaying and Interacting with Mass Difference Information: Application to Oligonucleotide Drug Impurities

Roussis

2015

J. Am. Soc. Mass Spectrom.

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Abstract.A new method is presented for determining relationships between components in complex analytical systems. The method uses the mass differences between peaks in high resolution electrospray ionization (ESI) mass spectra. It relates peaks that share common mass differences. The method is based on the fundamental assumption that peaks in the spectra having the same exact mass difference are related by the same chemical moiety/substructure. Moreover, the presence (or absence/loss) of the same chemical moiety from a series of molecules may reflect similarities in the mechanisms of formation of each molecule. The determined mass differences in the spectra are used to automatically differentiate the types of components in the samples. Contour plots and summary plots of the summed total ion signal as a function of the mass difference are generated, which form powerful tools for the rapid and automated determination of the components in the samples and for comparisons with other samples. For the first time, in this work a unique profile contour plot has been developed that permits the interactive interrogation of the mass range by mass difference data matrix to obtain valuable information about components that share a common mechanism of formation, and all possible mechanisms of formation linked to a selected precursor molecule. The method can be used as an additional and complementary method to the existing analytical methods to determine relationships between components in complex chemical systems.

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“…Phosphorothioate oligodeoxynucleotides are first generation antisense agents that have been widely used to modulate gene expression in cell-based assays, in animal models, and in the clinic (18). The phosphorothioate modification dramatically increases the nuclease resistance of the oligonucleotide and still supports RNase H activity (19). Further improvements to phosphorothioate oligodeoxynucleotides have been made, resulting in second generation oligonucleotides such as 2Ј-O-methyl or 2Ј-O-methoxyethyl modifications (15,20).…”

mentioning

confidence: 99%

Efficient Reduction of Target RNAs by Small Interfering RNA and RNase H-dependent Antisense Agents

Vickers

Koo

Bennett

et al. 2003

Journal of Biological Chemistry

426

291

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RNA interference can be considered as an antisense mechanism of action that utilizes a double-stranded RNase to promote hydrolysis of the target RNA. We have performed a comparative study of optimized antisense oligonucleotides designed to work by an RNA interference mechanism to oligonucleotides designed to work by an RNase H-dependent mechanism in human cells. The potency, maximal effectiveness, duration of action, and sequence specificity of optimized RNase H-dependent oligonucleotides and small interfering RNA (siRNA) oligonucleotide duplexes were evaluated and found to be comparable. Effects of base mismatches on activity were determined to be position-dependent for both siRNA oligonucleotides and RNase H-dependent oligonucleotides. In addition, we determined that the activity of both siRNA oligonucleotides and RNase H-dependent oligonucleotides is affected by the secondary structure of the target mRNA. To determine whether positions on target RNA identified as being susceptible for RNase H-mediated degradation would be coincident with siRNA target sites, we evaluated the effectiveness of siRNAs designed to bind the same position on the target mRNA as RNase H-dependent oligonucleotides. Examination of 80 siRNA oligonucleotide duplexes designed to bind to RNA from four distinct human genes revealed that, in general, activity correlated with the activity to RNase H-dependent oligonucleotides designed to the same site, although some exceptions were noted. The one major difference between the two strategies is that RNase H-dependent oligonucleotides were determined to be active when directed against targets in the pre-mRNA, whereas siRNAs were not. These results demonstrate that siRNA oligonucleotide-and RNase Hdependent antisense strategies are both valid strategies for evaluating function of genes in cell-based assays.

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Phosphorothioate Oligodeoxynucleotides: What Is Their Origin and What Is Unique About Them?

Cited by 357 publications

References 40 publications

A phosphorothioate antisense oligodeoxynucleotide specifically inhibits coxsackievirus B3 replication in cardiomyocytes and mouse hearts

A phosphorothioate antisense oligodeoxynucleotide specifically inhibits coxsackievirus B3 replication in cardiomyocytes and mouse hearts

A Novel and Intuitive Method of Displaying and Interacting with Mass Difference Information: Application to Oligonucleotide Drug Impurities

Efficient Reduction of Target RNAs by Small Interfering RNA and RNase H-dependent Antisense Agents

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