Beyond ribose and phosphate: Selected nucleic acid modifications for structure-function investigations and therapeutic applications

Over the past 25 years, the acceleration of achievements in the development of oligonucleotide-based therapeutics has resulted in numerous new drugs making it to the market for the treatment of various diseases. Oligonucleotides with alterations to their scaffold, prepared with modified nucleosides and solid-phase synthesis, have yielded molecules with interesting biophysical properties that bind to their targets and are tolerated by the cellular machinery to elicit a therapeutic outcome. Structural techniques, such as crystallography, have provided insights to rationalize numerous properties including binding affinity, nuclease stability, and trends observed in the gene silencing. In this review, we discuss the chemistry, biophysical, and structural properties of a number of chemically modified oligonucleotides that have been explored for gene silencing.

Automated summary

Over the past 25 years, there has been significant acceleration in the development of oligonucleotide-based therapeutics, leading to the market approval of many new drugs for treating various diseases. Chemically modified oligonucleotides with interesting biophysical properties that can bind to targets and be tolerated by cellular machinery have been explored for gene silencing.