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Keywords:
antisense oligonucleotides; chemically modified nucleotides; siRNAs
RNA-targeting oligonucleotides (e.g.. antisense. siRNA, and anti-miR) are widely explored as fundamental research tools and are gaining increasing promise as therapeutic agents, particularly against diseases of genetic origin. The idea of treating a disease by targeting the molecular messenger (mRNA) to stop the synthesis of proteins using short strands of DNA. now known as antisense oligonucleotides, was first coined about 40 years ago [1]. Almost 20 years later, another endogenous mechanism, known as RNA interference (RNAi) was discovered when it was shown that short stretches of double-stranded nucleotides, which are called short interfering RNA or "siRNA." can target mRNA and prevent it from being translated to make proteins [2]. While the mechanism by which antisense oligonucleotides (single stranded oligonucleotide) and siRNA (short RNA duplexes) work are completely different, both of them target mRNA to disrupt protein synthesis. In the following text we will refer both antisense oligonucleotides and siRNAs collectively as therapeutic oligonucleotides.
More than 10 oligonucleotide drugs have received regulatory approval by the FDA and are now helping patients suffering from conditions that were previously seen as unbeatable. However. the road from bench to bedside for therapeutic oligonucleotides has not been straightforward. It took about four decades (from discovery of the antisense mechanism) to reach the point where it is now possible to treat previously undruggable conditions using therapeutic oligonucleotides. There were many challenges including, but not limited to. poor stability of unmodified DNA strands and short RNA duplexes in cells, large anionic charge, poor drug-like properties, and a tendency to bigger the immune response in the body. Chemists have been at forefront of solving...