Phosphorothioate Oligonucleotides as Potential Antiviral Compounds Against Human Immunodeficiency Virus and Herpes Viruses

Cheng, Yung‐Chi; Gao, Weiyi; Han, Fu-Sheng

doi:10.1080/07328319108046443

Cited by 14 publications

(3 citation statements)

References 11 publications

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“…These proteins tend not only to bind PS-ODNs with much lower dissociation constants than unmodified ODNs but may perturb their function (29). Similarly, enzymes such as HIV-RT or HIV-RT-associated RNase H can be inhibited by PS-ODNs in a sequence-independent manner (30,31).…”

Section: Discussionmentioning

confidence: 99%

Telomerase protein rather than its RNA is the target of phosphorothioate-modified oligonucleotides

Matthes

Lehmann

1999

Nucleic Acids Research

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Human telomerase is a ribonucleoprotein which uses its internal RNA moiety as a template for telomeric DNA synthesis. This enzyme is up-regulated in most malignant tumors and is therefore considered as a possible cancer target. Here we examined the effects of differently modified oligomers on telomeraseactivity from HL-60 cell extracts (TRAP-ezetrade mark assay). Phosphorothioate-modified oligonucleotides (PS-ODNs) inhibited telomerase activity at subnanomolar concen-trations and proved to be more efficient than peptide nucleic acids. In contrast to all the investigated oligomers, PS-ODNs were found to bind to the protein motif of telomerase called the primer binding site but poorly to its RNA. This is suggested by kinetic investigations demonstrating a competitive interaction of PS-ODNs and TS primer at the primer binding site. The K m value of the TS primer was 10.8 nM, the K i value of a 20mer PS-ODN was 1.6 nM. When the TS primer was PS-modified a striking increase in the telomerase activity was found which correlates with the number of phosphodiesters replaced. The K m value of a completely PS-modified TS primer was 0.56 nM. Based on these results the design of chimeric ODNs is proposed consisting of a 5'-PS-modified part targeting the primer binding site and a 3'-terminus part targeting the telomerase RNA.

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Section: Discussionmentioning

confidence: 99%

Telomerase protein rather than its RNA is the target of phosphorothioate-modified oligonucleotides

Matthes

Lehmann

1999

Nucleic Acids Research

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“…Human DNA polymerases (DNA pols) are also inhibited by Sd(C)2 (2y > a> P) (89,90). The viral RT-associated RNase H activity was also sensitive to Sd(C)28, but its associated DNA-dependent DNA polymerase activity was not (91).…”

Section: Ps Oligos As Antiviral Agentsmentioning

confidence: 99%

Antisense Oligonucleotides as Therapeutic Agents—Is the Bullet Really Magical?

Stein

Cai²

1993

Science

1,283

633

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Because of the specificity of Watson-Crick base pairing, attempts are now being made to use oligodeoxynucleotides (oligos) in the therapy of human disease. However, for a successful outcome, the oligo must meet at least six criteria: (i) the oligos can be synthesized easily and in bulk; (ii) the oligos must be stable in vivo; (iii) the oligos must be able to enter the target cell; (iv) the oligos must be retained by the target cell; (v) the oligos must be able to interact with their cellular targets; and (vi) the oligos should not interact in a non-sequence-specific manner with other macromolecules. Phosphorothioate oligos are examples of oligos that are being considered for clinical therapeutic trials and meet some, but not all, of these criteria. The potential use of phosphorothioate oligos as inhibitors of viral replication is highlighted.

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“…These proteins are able to bind PS ODNs with high affinity, which might influence their function (Rockwell et al, 1997). Similarly, such enzymes as HIV-RT or its associated RNase H can be inhibited by PS ODNs in a widely sequence-independent manner (Majumder et al, 1989;Cheng et al, 1991). Human telomerase appears to be a further example of a heparin-binding protein that is inhibited very strongly by PS ODNs in a largely sequenceindependent manner (Norton et al, 1996;Matthes and Lehmann, 1999).…”

Section: Backbone Structure Of the 3ј-extensions Of Ps-odnsmentioning

confidence: 99%

Potent Inhibitory Activity of Chimeric Oligonucleotides Targeting Two Different Sites of Human Telomerase

Matthes¹,

Lehmann²,

Stulich³

et al. 2005

Oligonucleotides

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Suppression of telomerase activity in tumor cells has been considered as a new anticancer strategy.Here, we present chimeric oligonucleotides (chimeric ODNs) as a new type of telomerase inhibitor that contains differently modified oligomers to address two different sites of telomerase: the RNA template and a suggested protein motif. We have shown previously that phosphorothioate-modified oligonucleotides (PS ODNs) interact in a length-dependent rather than in a sequence-dependent manner, presumably with the protein part of the primer-binding site of telomerase, causing strong inhibition of telomerase. In the present study, we demonstrate that extensions of these PS ODNs at their 3-ends with an antisense oligomer partial sequence covering 11 bases of the RNA template cause significantly increased inhibitory activity, with IC 50 values between 0.60 and 0.95 nM in a Telomeric Repeat Amplification Protocol (TRAP) assay based on U-87 cell lysates. The enhanced inhibitory activity is observed regardless of whether the antisense part is modified (phosphodiester, PO; 2-O-methylribosyl, 2-OMe/PO; phosphoramidate, PAM). However, inside intact U-87 cells, these modifications of the antisense part proved to be essential for efficient telomerase inhibition 20 hours after transfection. In particular, the chimeric ODNs containing PAM or 2-OMe/PO modifications, when complexed with lipofectin, were most efficient telomerase inhibitors (ID 50 ‫؍‬ 0.04 and 0.06 M, respectively). In conclusion, ODNs of this new type emerged as powerful inhibitors of human telomerase and are, therefore, promising candidates for further investigations of the anticancer strategy of telomerase inhibition.

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Phosphorothioate Oligonucleotides as Potential Antiviral Compounds Against Human Immunodeficiency Virus and Herpes Viruses

Cited by 14 publications

References 11 publications

Telomerase protein rather than its RNA is the target of phosphorothioate-modified oligonucleotides

Telomerase protein rather than its RNA is the target of phosphorothioate-modified oligonucleotides

Antisense Oligonucleotides as Therapeutic Agents—Is the Bullet Really Magical?

Potent Inhibitory Activity of Chimeric Oligonucleotides Targeting Two Different Sites of Human Telomerase

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