An ab initio study of phosphorothioate and phosphorodithioate interactions with sodium cation

Volk, David E.; Power, Trevor D.; Gorenstein, David G.; Luxon, Bruce A.

doi:10.1016/s0040-4039(02)00850-x

Cited by 19 publications

(15 citation statements)

References 33 publications

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“…The result seen in Figure 1 indicates that the two mentioned opposite effects evidently cancel each other. Indeed, in a recent ab initio study36 of the interactions between phosphorothioate or phosphorodithioate and the, also “hard”, Na + ion it is concluded that a large destabilizing effect occurs only with the second sulfur substitution.…”

Section: Resultsmentioning

confidence: 99%

Complex Formation of Divalent Metal Ions with Uridine 5′‐O‐Thiomonophosphate or Methyl Thiophosphate: Comparison of Complex Stabilities with Those of the Parent Phosphate Ligands

2003

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The stability constants of the 1:1 complexes formed in aqueous solution between Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Zn2+, or Cd2+ (M2+) and methyl thiophosphate (MeOPS(2-)) or uridine 5'-O-thiomonophosphate (UMPS(2-)) (PS(2-)=MeOPS(2-) or UMPS(2-)) have been determined (potentiometric pH titrations; 25 degrees C; I = 0.1 M, NaNO(3)). Comparison of these results for M(PS) complexes with those known for the parent M(PO) phosphate species, where PO(2-)=CH(3)OPO(2-)(3) or UMP(2-) (uridine 5'-monophosphate), shows that the alkaline earth metal ions, as well as Mn2+, Co2+, and Ni2+ have a higher affinity for phosphate groups than for their thio analogues. However, based on the linear log K(M)(M(R-PO3)) versus pK(H)(H(R-PO3)) relationships (R-PO(2-)(3) simple phosphate monoester or phosphonate ligands with a non-interacting residue R) it becomes clear that the indicated observation is only the result of the lower basicity of the thiophosphate residue. In contrast, the thio complexes of Zn2+ and Cd2+ are more stable than their parent phosphate ones, and this despite the lower basicity of the PS(2-) ligands. This stability increase is identical for M(MeOPS) and M(UMPS) species and amounts to about 0.6 and 2.4 log units for Zn(PS) and Cd(PS), respectively. Since no other binding site is available in MeOPS(2-), this enhanced stability has to be attributed to the S atom. Indeed, from the mentioned stability differences it follows that Cd2+ in Cd(PS) is coordinated by more than 99% to the thiophosphate S atom; the same value holds for Pb(PS), which was studied earlier. The formation degree of the Sbonded isomer amounts to 76+/-6 % for Zn(PS) and is close to zero for the corresponding Mg2+, Ca2+, and Mn2+ species. It is further shown that Zn(MeOPS)(aq)(2+) releases a proton from a coordinated water molecule with pK(a) approximately 6.9; i.e., this deprotonation occurs at a lower pH value than that for the same reaction in Zn(aq)(2+). Since Mg2+, Ca2+, Mn2+, and Cd2+ have a relatively low tendency for hydroxo complex formation, it was possible, for these M2+, to also quantify the stability of the binuclear complexes, M(2)(UMPS-H)+, where one M2+ is thiophosphate-coordinated and the other is coordinated at (N3)(-) of the uracil residue. The impact of the results presented herein regarding M2+/nucleic acid interactions, including those of ribozymes (rescue experiments), is briefly discussed.

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Section: Resultsmentioning

confidence: 99%

Complex Formation of Divalent Metal Ions with Uridine 5′‐O‐Thiomonophosphate or Methyl Thiophosphate: Comparison of Complex Stabilities with Those of the Parent Phosphate Ligands

2003

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“…In this work, it was shown that the binding characteristics of phosphorodithioates [ 105 ] were superior to both phosphoromonothioates and phosphate-only versions of CK14 and that structural changes occur in the DNA with the duplex taking on a more A-DNA-like structure [ 106 ]. Later ab initio calculations suggested that decreased binding of sodium atoms to the thioated phosphates may account for the increased binding properties of phosphorothioates and phosphorodithioates [ 107 ]. Marshall and Caruthers had also demonstrated previously that phosphorodithioate DNA oligomers strongly inhibit human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT), relative to non-thioated oligonucleotides [ 108 ].…”

Section: Thioaptamer Developmentmentioning

confidence: 99%

Development of Phosphorothioate DNA and DNA Thioaptamers

Volk

Lokesh

2017

Biomedicines

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Nucleic acid aptamers are short RNA- or DNA-based affinity reagents typically selected from combinatorial libraries to bind to a specific target such as a protein, a small molecule, whole cells or even animals. Aptamers have utility in the development of diagnostic, imaging and therapeutic applications due to their size, physico-chemical nature and ease of synthesis and modification to suit the application. A variety of oligonucleotide modifications have been used to enhance the stability of aptamers from nuclease degradation in vivo. The non-bridging oxygen atoms of the phosphodiester backbones of RNA and DNA aptamers can be substituted with one or two sulfur atoms, resulting in thioaptamers with phosphorothioate or phosphorodithioate linkages, respectively. Such thioaptamers are known to have increased binding affinity towards their target, as well as enhanced resistance to nuclease degradation. In this review, we discuss the development of phosphorothioate chemistry and thioaptamers, with a brief review of selection methods.

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“…One explanation for the higher affinity of the thiosubstituted ONs is the poor cation co-ordination of the polyanionic backbone [7]. Sulfur, being a soft anion, does not co-ordinate as well to hard cations such as Na + , unlike the hard phosphate oxyanion.…”

Section: Thioaptamersmentioning

confidence: 99%

Combinatorial selection and delivery of thioaptamers

Thiviyanathan

Somasunderam

Gorenstein

2007

Biochemical Society Transactions

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Oligonucleotide-based agents are emerging as potential therapeutic agents that can be attractive alternatives for the small-molecule chemical drugs. Monothiophosphate-backbone-modified DNA aptamers (thioaptamers) that specifically and tightly bind to the RNase H domain of the HIV RT (reverse transcriptase) have been isolated from nucleic acid libraries using combinatorial selection methods. The selected thioaptamer inhibited RNase H activity of the HIV RT in in vitro studies. In cell cultures, the transfected thioaptamer markedly reduced HIV production in a dose-dependent manner. Gel electrophoretic mobility-shift assays and NMR spectroscopy showed that the selected thioaptamer binds to the isolated RNase H domain, but did not bind to a structurally similar RNase H from Escherichia coli. In cell cultures, the transfected thioaptamer showed a dose-dependent inhibition of HIV replication, with a maximal inhibition of 83%. Using various liposome-delivery agents, the DNA thioaptamer was transfected into HIV-infected astrocytoma adherent cells with greater than 70% efficiency.

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An ab initio study of phosphorothioate and phosphorodithioate interactions with sodium cation

Cited by 19 publications

References 33 publications

Complex Formation of Divalent Metal Ions with Uridine 5′‐O‐Thiomonophosphate or Methyl Thiophosphate: Comparison of Complex Stabilities with Those of the Parent Phosphate Ligands

Complex Formation of Divalent Metal Ions with Uridine 5′‐O‐Thiomonophosphate or Methyl Thiophosphate: Comparison of Complex Stabilities with Those of the Parent Phosphate Ligands

Development of Phosphorothioate DNA and DNA Thioaptamers

Combinatorial selection and delivery of thioaptamers

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