Oligonucleotides

 

Oligonucleotide Analysis | Thermo Fisher Scientific - KR

 

About Oligonucleotide Therapeutics

Oligonucleotide therapeutics are short, single- or double-stranded DNA or RNA molecules that bind via Watson-Crick base pairing to enhance or repress the expression of target RNA, in order to treat or manage a wide range of diseases. They include, Antisense oligonucleotides (ASOs), RNA interference (RNAi), and aptamers.

 Oligonucleotide therapeutic principle

Oligonucleotide and RNA therapies expand the range of drug targets beyond traditional protein based biotherapeutics, to include DNA and RNA:

Guide RNA can be used to directly edit gene sequences, RNAs (asRNA, siRNA, miRNA) target mRNA and ncRNA, RNA aptamers block protein targets. 

Therapeutic Oligonucleotide Control of Disease

 

 

 Antisense oligonucleotides (ASO)

ASOs match the complementary sequence of a specific mRNA. ASO can have two different effects on the mRNA. Some modifications of ASOs trigger the destruction of the mRNA. This will result in the loss of the corresponding protein. Other modifications can mask only certain parts of the mRNA leading to a modified version of the protein.

 RNA interference

RNA molecules inhibit gene expression or translation, by neutralizing targeted mRNA molecules

 

 

Aptamer

Target recognition and binding of aptamers involves three-dimensional, shape-dependent interactions as well as hydrophobic interactions, base-stacking, and intercalation. Aptamers bind to a portion of their target in which they fit.

To date, oligonucleotide therapeutics have focused on gene silencing other strategies are being pursued, these including gene activation and splice modulation strategies which have the potential to expand therapeutics targets beyond what is generally accessible to conventional pharmaceutical modalities.

There are hundreds of oligonucleotide therapies currently in clinical development with several gaining regulatory approval. Despite this, difficulties remain in achieving efficient delivery to target organs and tissues.

The most commonly used strategies employed to improve nucleic acid drug delivery include chemical modification to improve ‘drug-likeness’, covalent conjugation to cell-targeting or cell-penetrating moieties and nanoparticle formulation, endogenous vesicle (exosome) loading, spherical nucleic acids (SNAs), nanotechnology applications (DNA cages).

 

 

 

Chemical Modifications

Common chemical modifications used in oligonucleotide drugs

In addition to ensuring oligonucleotide therapeutic modifications occurred as intended, one must also monitor for impurities that occur during oligonucleotide synthesis. Such as:

• N-1, N-2 from failed sequences
• N+1
• PO backbone reversion
• De-protection (DMT)
• Deamination of base
• Depurination of base
• Distereoisomer of PS backbone