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Phosphorothioates (PTOs) are the most widely used nuclease resistant oligonucleotides (oligos) for antisense applications. Creative Biolabs provides customer-oriented oligonucleotide synthesis with phosphorothioate modification.


There are two major challenges involved in oligos in vivo applications. The first one is delivery to the interior of the cell through the plasma membrane, a lipid bilayer without transport proteins, which is mostly impermeable to polar molecules. The second one is the extension of the effective molecular lifetime by minimizing extra and intracellular nuclease degradation.

Several phosphate backbone variants have been advanced in an attempt to alter the chemical properties of native-state DNA. One of the original and still most widely-used backbone variants is phosphorothioate. Phosphorothioates (Figure 1) have been found to help alleviate the major challenge associated with oligonucleotides by reducing the activity of a variety of extra and intracellular nucleases.

Mechanism of Phoshorothiates

Although the natural phosphodiester bonds are highly susceptible to rapid degradation by cellular nucleases, the modification of inter-nucleotide linkage using phosphorothioate bond substitutes is substantially more stable towards hydrolysis by cellular degradation. The phosphorothioate enhanced RNA oligomer has shown to inhibit RNase A, RNase T1 and calf serum nucleases. These properties allow the use of PS-RNA oligo to be used in the application where exposure to nucleases is inevitable in vivo or in vitro.

Phosphorothioate modification is a class of modified method that using the backbone linkage to modify the phosphodiester linkage to phosphorothioate. This affects considerable nuclease resistance and is used widely in the design of antisense oligos (ODN). Phosphorothioate bonds are available to be introduced between the last 3-5 nucleotides at the 5'- or 3'-end of the oligo to inhibit exonuclease degradation. Phosphorothioate bonds throughout the entire oligo will help reduce attack by endonucleases as well.

Phoshorothiates structure. Figure 1. Phoshorothiates structure. (Scotson, 2016)

Phosphorothioate Modification Services at Creative Biolabs

Creative Biolabs offers several kinds of phosphorothioates for oligonucleotide modification. Customers could select them based on their experiments. We also provide several different types of phosphorothioates for synthesizing bases, listed below:

Structures of several phosphorothioates. Figure 2. Structures of several phosphorothioates. (Shimo, 2014-A, C; Geary, 2001-B)

Phosphorothioate modification is effective at reducing the nucleolytic degradation of oligos needed for both in vivo and in vitro technologies. Creative Biolabs is a key supplier of RNA oligos synthesis and modification for pre-clinical research. We have optimized the synthesis and purification of RNA oligos to meet a variety of research and applied needs. Our team is here to support your RNA research through our expertise in high-quality nucleic acid synthesis with different modifications. If you have any special requirements in phosphorothioates, please feel free to contact us.


  1. Scotson, J.L.; et al. (2016). Phosphorothioate Anti-sense Oligonucleotides: The Kinetics and Mechanism of the Generation of the Sulfurising Agent from Phenylacetyl Disulfide (PADS). Organic & Biomolecular Chemistry. 14(35): 8301-308.
  2. Shimo, T.; et al. (2014). Design and Evaluation of Locked Nucleic Acid-based Splice-switching Oligonucleotides in Vitro. Nucleic Acids Research. 42(12): 8174-187.
  3. Geary, R.S.; et al. (2001). Pharmacokinetic Properties of 2'-O-(2-methoxyethyl)-modified Oligonucleotide Analogs in Rats. The Journal of Pharmacology and Experimental Therapeutics. 296(3): 890-897.

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