Oligonucleotide phosphorothioate

Bourque, A. J. and Cohen, A. S., Quantitative analysis of phosphorothioate oligonucleotides in biological fluids using fast anion-exchange chromatography, J. Chromatogr., 617, 43, 1993. 

A new antiviral agent, developed for treatment of CMV retinitis, can be administered by intravitreal injection. Formivirsen sodium is a phosphorothioate oligonucleotide that inhibits CMV replication through an antisense mechanism. It is formulated as a sterile and preservative-free solution and supplied in single-use vials (Vitravene ). The product is administered directly into the vitreous cavity posterior to the limbus through a 30-gauge needle. This procedure can be performed on an... 

Galbraith, W.M., Hobson, W.C., Giclas, PC., Schechter, P.J. and Agrawal, S. (1994). Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey. Antisense Res. Dev. 4 201-206. 

A variety of such phosphorothioate oligonucleotides have, thus, been reported in the literature [138-142], In one particularly illustrative study, the 20-mer phosphodiester oligonucleotide 5 -TCATGCTCATGCGCTCATGC-3 and its phosphorothioate congener were compared for their distribution... 

P. A. Cossum, H. Sasmor, D. Dellinger, L. Truong, L. Cummings, S. R. Owens, P. M. Markham, J. P. Shea, S. Crooke, Disposition of the 14C-Labeled Phosphorothioate Oligonucleotide ISIS 2105 after Intravenous Administration to Rats ,./. Pharmacol. Exp. Ther. 1993, 267, 1181-1190. 

A. General description Fomivirsen sodium (molecular weight about 7kDa) is a phosphorothioate oligonucleotide, 21 nucleotides in length, with the following sequence 5 -GCG TTT GCT CTT CTT CTT GCG-3. ... 

King, D.J., Ventura, D.A., Brasier, A.R. and Gorenstein, D.G. (1998) Novel combinatorial selection of phosphorothioate oligonucleotide aptamers. Biochemistry, 37,16489-16493. 

Figure 9.2 pH-Dependencies of the degree of conversion (7) in the polyion coupling reactions ( , ) and degree of ionization (a) of polybase samples (o, ) for the following systems PEO-g-PEI (curve l,o) PEO-g-PEI and 24-mer phosphorothioate oligonucleotide (curve 2, ). The pH-shift, ApEI, between the 0-pH and a-pi I dependencies is shown as an example. Based on the data reported by Vinogradov etal. (1998). 

Vinogradov, S.V., Bronich, T.K. and Kabanov, A.V. (1998) Self-assembly of polyamine-poly(ethylene glycol) copolymers with phosphorothioate oligonucleotides. Bioconjug. Chem., 9, 805-812. 

Peng, B., Andrews, J., Nestorov, I., Brennan, B., Nicklin, P. and Rowland, M. (2001) Tissue distribution and physiologically based pharmacokinetics of antisense phosphorothioate oligonucleotide ISIS 1082 in rat. Antisense Nucleic Acid Drug Develop., 11, 15-27. 

McIntyre, K.W., Lombard-Gillooly, K., Perez, J.R., Kunsch, C., Sarmiento, U.M., Larigan, J.D. et al. (1993) A sense phosphorothioate oligonucleotide directed to the initiation codon of transcription factor NF-kappa B p65 causes sequence-specific immune stimulation. Antisense Res. Dev., 3, 309-322. 

Pisetsky, D.S. and Reich, C.F. (1994) Stimulation of murine lymphocyte proliferation by a phosphorothioate oligonucleotide with antisense activity for herpes simplex virus. Life Sci., 54, 101-107. 

The term (XG + Xc) is the sum of the mole fractions of guanine and cytidine in the antisense strand. The mole fraction of any nucleobase is equal to the number of nucleotides containing that base divided by the total number of nucleotides in the oligonucleotide strand. [M+] is the molar concentration of monovalent cations. In a typical mammalian cell, [K + ] is 140 mM, and [Na+ ] is 10 mM. L is the length of the duplex in base pairs. Based on Equation 6.2 and the assumption that phosphorothioate oligonucleotides behave as regular DNA, fomivirsen (6.17) would have a predicted Tm of 59 °C. Equation 6.1 predicts 64 °C. More complex forms of Equation 6.2 with increased accuracy appear regularly in the literature.8... 

Fig. 4.1 Representations of the chemical structure offirst-generation oligonucleotides and 2/-MOE partially modified phosphorothioate oligonucleotides (second-generation oligonucleotides) (B = G, C,T, or A).

T. Burckin, L. Truong, and A.A. Levin. 1997. Pharmacokinetic properties of phosphorothioate oligonucleotides. Nucleosides Nucleotides 16 1689-1693. 

Disposition of the 14C-labeled phosphorothioate oligonucleotide ISIS 2105 after intravenous administration to rats. 

Pharmacokinetics of a 14C-labeled phosphorothioate oligonucleotide, ISIS 2105, after intradermal administration to rats./. Pharmacol. Exp. Ther. 269 ... 

Yu, R.Z., R.S. Geary, J.M. Leeds,T. Ushiro-Watanabe, M. Moore, J. Fitchett, J. Matson, T. Burckin, M.V. Templin, and A.A. Levin. 2001. Comparison of pharmacokinetics and tissue disposition of an antisense phosphorothioate oligonucleotide target-... 

P.J. Schechter. 1999. Pharmacokinetics and tolerability of intravenous trecovirsen (GEM 91), an antisense phosphorothioate oligonucleotide, in HIV-positive subjects. /. Clin. Pharmacol. 39 47-54. 

Leeds, J.M., and R.S. Geary. 1998. Pharmacokinetic properties of phosphorothioate oligonucleotides in humans. In ... 

L. L. Cummins. 1996. Quantitation of phosphorothioate oligonucleotides in human plasma. Anal. Biochem. 

Boado et al. [28] devised delivery systems based on conjugates of streptavidin and the 0X26 monoclonal antibody directed to the transferrin receptor as a carrier for the transport of ASO. These delivery systems were found to transport peptide nucleic acid antisense molecules, but not ASO, across the BBB. These authors attributed this difference to preferential binding of phosphorothioate oligonucleotide to plasma protein instead of the antibody complex, which reduced their transport. 

A. Zutsi, A.A. Levin, and D.J. Kornbmst. 1997. Pharmacokinetics of a potential human cytomegalovirus therapeutic, a phosphorothioate oligonucleotide, after intravitreal injections in the rabbit. Drug Metab. Dispos. 25 921-926. 

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