Structure-Activity Study of Oligodeoxynucleotides Which Inhibit Thrombin

Krawczyk, Steven H.; Bischofberger, Norbert; Griffin, Linda C.; Law, Veronica S.; Shea, Regan G.; Swaminathan, S.

doi:10.1080/15257779508012546

Cited by 18 publications

(29 citation statements)

References 2 publications

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“…NMR studies (Macaya et al, 1993;Wang et al, 1993a;Schultze et al, 1994) and mutational analysis (Krawczyk et al, 1995) of the G15D unimolecular G-quadruplex have indicated that the two conserved thymine residues at positions 4 and 13 are stacked to form a base-pair across the diagonal of the quartet. Substitution of T to A at position T 4 would no longer allow for the T 4 Á T 13 base-pair across the diagonal of the quartet, resulting in a destabilization of the quadruplex.…”

Section: Discussionmentioning

confidence: 99%

Oligonucleotide inhibitors of human thrombin that bind distinct epitopes

Tasset

Kubik

Steiner

1997

Journal of Molecular Biology

777

772

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Section: Discussionmentioning

confidence: 99%

Oligonucleotide inhibitors of human thrombin that bind distinct epitopes

Tasset

Kubik

Steiner

1997

Journal of Molecular Biology

777

772

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“…The results described in this article contribute further data to the structural features of the quadruplex with regards to the intricate relationship between the relative orientation of the strands, the glycosidic conformation of the G bases and the CD behaviour. Furthermore, the capacity of dG Me residues to stabilize parallel quadruplexes when present in specific positions may be of interest in the area of aptamers research whose core is often based upon quadruplex structures ( 38 ). In fact, a development of the SELEX process, the in vitro selection technique which utilizes combinatorial chemistry to produce ODN aptamers with high binding affinity and specificity towards a given target molecule, consists of modifications that can be introduced either into the initial randomized pool or subsequent to the selection of aptamer by chemical synthesis ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

8-Methyl-2'-deoxyguanosine incorporation into parallel DNA quadruplex structures

Virgilio

Esposito

Randazzo

et al. 2005

Nucleic Acids Research

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This paper concerns the Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) structural studies of the quadruple helix arrangements adopted by three tailored oligodeoxyribonucleotide analogues, namely d(TGMeGGT), d(TGGMeGT) and d(TGGGMeT), where dGMe represents a 8-methyl-2′-deoxyguanosine residue. The results of this study clearly demonstrate that the effects of the incorporation of dGMe instead of a dG residue are strongly dependant upon the positioning of a single base replacement along the sequence. As such, d(TGMeGGT), d(TGGMeGT) have been found to form 4-fold symmetric quadruplexes with all strands parallel and equivalent to each other, each more stable than their natural counterpart. NMR experiments clearly indicate that [d(TGMeGGT)]4 possesses a GMe-tetrad with all dGMe residues in a syn-glycosidic conformation while an anti-arrangement is apparent for the four dGMe of [d(TGGMeGT)]4. As the two complexes show a quite different CD behaviour, a possible relationship between the presence of residues adopting syn-glycosidic conformations and CD profiles is briefly discussed. As far as d(TGGGMeT) is concerned, NMR data indicate that at 25°C it exists primarily as a single-strand conformation in equilibrium with minor amounts of a quadruplex structure.

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“…Modifications stabilizing the tetrad structure increase the thrombin inhibitory activity, whereas modifications destabilizing the structure reduce the activity. 9,10 In the present study, however, replacing any of the 14 phosphodiester linkages in 1 with a neutral formacetal linkage does not dramatically affect the thrombin inhibitory activity. With the monosubstitutions, the maximum decrease was observed for T 13 -f-G 14 in 106 (relative PT ) 0.6).…”

Section: Resultsmentioning

confidence: 65%

In Vitro and in Vivo Activities of Oligodeoxynucleotide-Based Thrombin Inhibitors Containing Neutral Formacetal Linkages

Williams

Postich

et al. 1998

J. Med. Chem.

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A series of 15-mer oligodeoxynucleotide analogues were synthesized, and their thrombin inhibitory activities in vitro and in vivo were evaluated. These oligodeoxynucleotide analogues share the same sequence (GGTTGGTGTGGTTGG) but have one or more phosphodiester linkages replaced by a neutral formacetal group. The results obtained from monosubstitutions show that no single phosphodiester group is critical for the thrombin inhibitory activity, suggesting that the interaction between the oligodeoxynucleotide and thrombin is based on a multiple-site charge-charge interaction. Analysis of the effects of different phosphodiester replacements indicates that the backside and left side of the chairlike structure formed by the molecule may be involved in binding with thrombin, presumably by having direct contacts with the anion-binding exosite of the enzyme. For the oligodeoxynucleotides containing two noncontiguous formacetal groups, the effect of the disubstitution is the sum of the effects obtained from the corresponding two monosubstitutions. Infusion of an oligodeoxynucleotide containing four formacetal groups into monkeys showed an increased in vivo anticoagulant effect and an extended in vivo half-life compared to the unmodified oligodeoxynucleotide.

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Structure-Activity Study of Oligodeoxynucleotides Which Inhibit Thrombin

Cited by 18 publications

References 2 publications

Oligonucleotide inhibitors of human thrombin that bind distinct epitopes

Oligonucleotide inhibitors of human thrombin that bind distinct epitopes

8-Methyl-2'-deoxyguanosine incorporation into parallel DNA quadruplex structures

In Vitro and in Vivo Activities of Oligodeoxynucleotide-Based Thrombin Inhibitors Containing Neutral Formacetal Linkages

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