Thioaptamer
Thioaptamers are a class of nucleic acid (DNA or RNA) aptamers, in which some or all of the non-bridging oxygen atoms of phosphodiester bonds have been replaced by sulfur atoms in order to increase binding energies with proteins and to slow down degradation caused by nuclease enzymes, so that they may be used to bind to proteins and regulate functions within cells. At present, no Thioaptamer drugs have been approved for medical use, but a number of them have been designed to bind to NF-kB [1] and AP1[2] proteins which are key regulators of the immune system, and to viral envelope proteins associated with Venezuelan equine encephalitis virus[3] and the RNAse H domain of HIV-1 RT[4]. These agents are being actively studied.
Chemistry
Traditionally, DNA is synthesized by linking phosphoramites sequentially. If only one of the non-bridging oxygen atoms is replaced, standard DNA synthesis methods can be used, but instead of the standard oxidation step after the cooupling reaction, the Beaucage reagent is used to incorporate a single sulfur atom. If both non-bridging oxygen atoms are to be replaced, thiophosphoramidites, rather than phosphoramidites, are used to provide the first sulfur atom, and subsequent oxidation with the Beaucage reagent provides the second sulfur atom. The chemistry required to synthesize DNA with the incorporation of two sulfur atoms was developed independently by research groups headed by David G. Gorenstein and Marvin H. Caruthers in 1988, and the methods have subsequently been greatly improved [5].
references
- ↑ Volk, D. E., Yang, X., Fennewald, S. M., King, D. J., Bassett, S. E., Venkitachalama, S., Herzog, N., Luxon, B. A. and Gorenstein, D. G. (2002). "Solution structure and design of dithiophosphate backbone aptamers targeting transcription factor NF-κB". Bioorg. Chem. 30: 396-419. [1]
- ↑ S. M. Fennewald, E. P. Scott, L. H. Zhang, J. F. Aronson, D. G. Gorenstein, B. A. Luxon, R. E. Shope, D. W. C. Beasley and N. K. Herzog (2007). "Thioaptamer Decoy Targeting AP-1 Proteins Influences Cytokine Expression and the Outcome of Arenavirus Infections.". J. Gen. Virol. 88: 981-990. [2]
- ↑ Kang, J., Lee, M., Watowich, S. and Gorenstein, D. G. (2007). "Combinatorial selection of a RNA thioaptamer that binds to Venezuelan equine encephalitis virus capsid protein". FEBS Letters 581: 2497-2502. [3]
- ↑ M. R. Ferguson, D. R. Rojo, A. Somasunderam, V. Thiviyanathan, B. Ridley, X. Yang and D.G. Gorenstein (2006). "Delivery of double-stranded DNA thioaptamers into HIV-1 infected cells for antiviral activity". Biochem. Biophys. Res. Commun. 344: 792-797. [4]
- ↑ Wieslert, W. T. and Caruthers, M. H. (1996). "Synthesis of Phosphorodithioate DNA via Sulfur-Linked, Base-Labile Protecting Groups". J. Org. Chem. 61: 4272-4281. [5]