Oligonucleotide therapeutics Phosphorothioate oligonucleotides

A supported sulfide source has been demonstrated by Zhang et al.16 to synthesize oligonucleotide phosphorothioates (entry 12). Aminodithiazole-thione attached to a methacrylate-ethyleneglycol copolymer is used to efficiently convert a nucleotide phosphite to a phosphorothioate. The product nucleotide possesses protecting groups suitable for solid-phase oligonucleotide synthesis and thus is a valuable building block for nucleic acid therapeutics. 

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. 

Cossum PA, Sasmor H, Dellinger D, Truong L, Cummins L, Owens SR, Markham PM, Shea JP, Crooke ST. Disposition of the 14C-labeled phosphorothioate oligonucleotide ISIS 2105 after intravenous administration to rats. J Pharmacol Exp Therapeut 1993 267(3) 1181—90. 

Henry SP, Giclas PC, Leeds J, Pangburn M, Auletta C, Levin AA, Kornbrust DJ. Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide potential mechanism of action. J Pharmacol Exp Therapeut 1997 281(2) 810-6. 

Graham MJ, Crooke ST, Monteith DK, Cooper SR, Lemonidis KM, Stecker KK, Martin MJ, Crooke RM. In vivo distribution and metabolism of a phosphorothioate oligonucleotide within rat liver after intravenous administration. J Pharmacol Exp Therapeut 1998 286(l) 447-58. 

Phosphorothioate oligonucleotides have perhaps outperformed many expectations. They display attractive parenteral pharmacokinetic properties. They have produced potent systemic effects in a number of animal models and, in many experiments, the antisense mechanism has been directly demonstrated as the hoped-for selectivity. Further, these compounds appear to display satisfactory therapeutic indices for many indications. 

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