Progress in antisense technology: The end of the beginning

Crooke, Stanley T.

doi:10.1016/s0076-6879(00)13003-4

Cited by 161 publications

(95 citation statements)

References 112 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%

“…41 Moreover, in vivo pharmacokinetic and distribution studies have shown that free PS AS-ODNs are well absorbed from parenteral sites and distribute broadly to organs and peripheral tissues via intravenous administration. 23,36 Further, efficient cellular uptake of AS-ODNs in vivo has been achieved without the use of any delivery system. 42 Currently, eight PS AS-ODNs are being investigated in phase II and III clinical trials for a broad range of diseases, including viral infections, cancer and inflammatory diseases.…”

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

confidence: 99%

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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%

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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“…This is a major reason why they have been widely investigated as potential therapeutic agents for cancer, viral infections, and inflammatory diseases. Oligonucleotides can achieve target recognition by sequence-specific interactions with nucleic acids or proteins such as in the antisense, antigene, or decoy approaches (1)(2)(3)(4). Alternatively, target recognition can be due to the specific threedimensional structure of an oligonucleotide, as in the aptamer approach (5,6).…”

mentioning

confidence: 99%

Inhibition of DNA Replication and Induction of S Phase Cell Cycle Arrest by G-rich Oligonucleotides

Hamhouyia²,

Thomas³

et al. 2001

Journal of Biological Chemistry

154

161

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The discovery of G-rich oligonucleotides (GROs) that have non-antisense antiproliferative activity against a number of cancer cell lines has been recently described. This biological activity of GROs was found to be associated with their ability to form stable G-quartet-containing structures and their binding to a specific cellular protein, most likely nucleolin (Bates, P. J., Kahlon, J. B., Thomas, S. D., Trent, J. O., and Miller, D. M. (1999) J. Biol. Chem. 274, 26369 -26377). In this report, we further investigate the novel mechanism of GRO activity by examining their effects on cell cycle progression and on nucleic acid and protein biosynthesis. Cell cycle analysis of several tumor cell lines showed that cells accumulate in S phase in response to treatment with an active GRO. Analysis of 5-bromodeoxyuridine incorporation by these cells indicated the absence of de novo DNA synthesis, suggesting an arrest of the cell cycle predominantly in S phase. At the same time point, RNA and protein synthesis were found to be ongoing, indicating that arrest of DNA replication is a primary event in GRO-mediated inhibition of proliferation. This specific blockade of DNA replication eventually resulted in altered cell morphology and induction of apoptosis. To characterize further GRO-mediated inhibition of DNA replication, we used an in vitro assay based on replication of SV40 DNA. GROs were found to be capable of inhibiting DNA replication in the in vitro assay, and this activity was correlated to their antiproliferative effects. Furthermore, the effect of GROs on DNA replication in this assay was related to their inhibition of SV40 large T antigen helicase activity. The data presented suggest that the antiproliferative activity of GROs is a direct result of their inhibition of DNA replication, which may result from modulation of a replicative helicase activity.Oligonucleotides can recognize both nucleic acids and proteins with a high degree of specificity. This is a major reason why they have been widely investigated as potential therapeutic agents for cancer, viral infections, and inflammatory diseases. Oligonucleotides can achieve target recognition by sequence-specific interactions with nucleic acids or proteins such as in the antisense, antigene, or decoy approaches (1-4). Alternatively, target recognition can be due to the specific threedimensional structure of an oligonucleotide, as in the aptamer approach (5, 6). These aptameric oligonucleotides often contain secondary structure elements such as hairpins or G-quartets. The formation of G-quartet structures is also thought to contribute to non-antisense growth inhibitory effects of G-rich phosphodiester and phosphorothioate oligonucleotides (7-9).Recently, we reported (9) on a novel class of phosphodiester G-rich oligonucleotides (GROs) 1 that could strongly inhibit the in vitro proliferation of tumor cells derived from prostate, breast, and cervical carcinomas. The antiproliferative GROs were able to form stable secondary structures consistent with G-quartet format...

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“…Secondary-structure mapping of the negative-strand 3Ј terminus has yet to be reported, but the sequence has been predicted to form various stem-loop structures (3,31,36). Mutational analysis suggests that binding of the HCV NS3 helicase to this region is sensitive to both the primary and secondary structure of a proposed terminal stem-loop (3).The essential replicative functions and strict sequence conservation of HCV UTRs make these elements and their negative-strand complements promising targets for the development of antisense nucleic acid inhibitors (12,51). Numerous studies (reviewed in reference 24) have explored the development of oligodeoxynucleotide (ODN) and ribozyme constructs targeting the HCV 5Ј-UTR and adjacent core protein N-terminal coding sequence, as antisense-mediated binding or cleavage of this region can inhibit IRES-directed gene expression.…”

mentioning

confidence: 99%

Secondary structure and hybridization accessibility of the hepatitis C virus negative strand RNA 5′‐terminus

Smith

2004

Journal of Viral Hepatitis

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The 3 -terminal sequences of hepatitis C virus (HCV) positive-and negative-strand RNAs contribute cis-acting functions essential for viral replication. The secondary structure and protein-binding properties of these highly conserved regions are of interest not only for the further elucidation of HCV molecular biology, but also for the design of antisense therapeutic constructs. The RNA structure of the positive-strand 3 untranslated region has been shown previously to influence binding by various host and viral proteins and is thus thought to promote HCV RNA synthesis and genome stability. Recent studies have attributed analogous functions to the negative-strand 3 terminus. We evaluated the HCV negative-strand secondary structure by enzymatic probing with single-strand-specific RNases and thermodynamic modeling of RNA folding. The accessibility of both 3 -terminal sequences to hybridization by antisense constructs was evaluated by RNase H cleavage mapping in the presence of combinatorial oligodeoxynucleotide libraries. The mapping results facilitated identification of antisense oligodeoxynucleotides and a 10-23 deoxyribozyme active against the positivestrand 3 -X region RNA in vitro.The untranslated regions (UTRs) of the hepatitis C virus (HCV) positive-strand genome and negative-strand intermediate contain cis-acting sequences essential for viral translation and RNA replication. The 341-nucleotide (nt) 5Ј-UTR of the positive strand acts as an internal ribosome entry site (IRES) to direct cap-independent translation of the single ϳ3,000-codon-long HCV open reading frame (38, 40). The tripartite 3Ј-UTR consists of a short upstream variable region, a central poly(U)-polypyrimidine stretch of variable length, and a terminal highly conserved 98-nt sequence (38). With the exception of the variable region, all sequence elements in the 3Ј-UTR are necessary for intracellular replication of HCV RNA (16,29,56).A number of in vitro studies (26,35,36,39,58) have established that the terminal 98-nt X region sequence can serve as a minimal template for de novo initiation of negative-strand synthesis by the viral RNA-dependent RNA polymerase, NS5B. The 3Ј terminus of the HCV negative strand reportedly plays an analogous role in positive-strand RNA synthesis (25,36,39). The binding of HCV 3Ј termini to various host proteins may exert subtle effects on IRES-mediated translation (16,23,34,55) or protect viral transcripts from degradation by cytoplasmic RNases (15,48,49).The replicative and protein-binding functions of heteropolymeric regions in the HCV 3Ј termini are, in many instances, dependent on the ability of the primary sequence to fold into higher-order RNA structure. In vitro, the X region sequence is capable of adopting a three-stem-loop structure, with the 3Ј-terminal 46 nt forming a thermodynamically stable stem-loop, SL I (6). Mutational analysis indicates that the duplex structure forming the base of SL I influences both the site and efficiency of de novo initiation by NS5B (26,35). Preservation of the interior stem-...

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Progress in antisense technology: The end of the beginning

Cited by 161 publications

References 112 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

Inhibition of DNA Replication and Induction of S Phase Cell Cycle Arrest by G-rich Oligonucleotides

Secondary structure and hybridization accessibility of the hepatitis C virus negative strand RNA 5′‐terminus

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