Antisense Oligonucleotides Make Sense

by Liana Relina Contributor , Illia Petrov  

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Antisense oligonucleotides (ASOs) are short (about 12 to 25 nucleotides long), synthetic single strands of DNA or RNA that are complementary to a chosen sequence. They can alter RNA and reduce, restore, or modify protein expression. ASOs interact with proteins on the surface of cells and enter the cytoplasm. Then they can work either in right in the cytoplasm or enter the nucleus.

In their naked form, ASOs cannot permeate the plasma membrane and are highly sensitive to degradation by endonucleases and exonucleases. To overcome these problems, ASOs have been chemically modified. On the basis of these modifications, ASOs can be broadly classified into three generations.

  1. In first-generation ASOs, the phosphate backbone linking the nucleotides is modified. One of the non-bridging oxygen atoms in the phosphodiester bond is replaced by a sulfur, methyl or amine group. These chemical modifications have improved the ASO stability by increasing the resistance of ASOs to nucleases. Unfortunately, the biologically active modified ASOs are highly toxic due, in particular, to their non-specific binding to proteins. This led researchers to develop new generations of ASOs that were both less toxic and more specific.

  2. The second generation of ASOs is characterized by alkyl modifications at the 2′ position of the ribose. These ASOs are less toxic and have a slightly higher affinity for their target.

  3. The third generation is more heterogeneous because it includes a large number of modifications aiming to improve binding-affinity, resistance to nucleases, and pharmacokinetic profile. The most common modifications include locked nucleic acids; phosphorodiamidate morpholino oligomers, in which the ribose is replaced by a morpholine moiety and the phosphodiester bond by a phosphorodiamidate bond; and peptide nucleic acids, in which the ribose-phosphate backbone is replaced by a polyamide backbone.

 

Several distinct mechanisms of ASOs are known:

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Topics: Biotech   

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