eISSN: 2221-6197 DOI: 10.31301/2221-6197

Chemical synthesis of oligonucleotides: stages of a 70-year journey

Year: 2026

Pages: 178-214

Number: Volume 18, issue 2

Type: scientific article

Summary:

More than 70 years ago, in August 1955, an article was published describing the first synthesis of dinucleotides with a natural phosphodiester bond. Over the years, the chemical synthesis of oligonucleotides has undergone a serious evolution, going through various stages from phosphotriester, through phosphonate, phosphodiester, phosphite triester, and then transformed into phosphoramidite. The latter approach is currently the main method of synthesis of oligonucleotides using automatic DNA synthesizers. In general, the phosphoramidite method provides solutions to current scientific and practical problems, with the exception of the production of extended oligonucleotides and large-scale synthesis. However, the demand for oligonucleotides will inevitably grow, including in their modified forms, both in terms of diversity and quantity. At the same time, both solid-phase column and microarray syntheses, as well as synthesis in the liquid phase, capable of producing kilogram amounts of therapeutic oligonucleotides, will have to be intensively developed. It can be predicted that the demand for relatively short oligonucleotides for agriculture will be measured in tons after a while.

Keywords:

oligonucleotide, chemical synthesis of oligonucleotides, amidophosphite method, DNA synthesizer, solid-phase column synthesis, microarray synthesis, synthesis of oligonucleotides in the liquid phase

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