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

Abstract

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.

The Characterization of Substructures of γ‐Anti Fuzzy Subgroups with Application in Genetics

“…ese triplets are called standard genetic code SGC [35]. It is a domain transformation of crisp into fuzzy inputs that are used to establish the degree of truth for each rule premise.…”

Influence of Sugar Modifications on the Nucleoside Conformation and Oligonucleotide Stability: A Critical Review

“…Chemically modified phosphodiester backbone, ribofuranose sugar moieties, and nucleobases have been incorporated into these oligonucleotides to improve drug-like properties such as thermal, serum stability, and permeability as well as to reduce off-target effects, and undesired immunogenic responses. [32][33][34] Possibility of siRNA as drugs became true employing potential delivery systems. Chemical modifications and delivery systems are key for moving siRNA into the market as drugs.…”

“…The most important and successful phosphodiester modification is the phosphorthioate (sulfur atom replacing one of the non-bridging oxygen atoms in the backbone) which enhances the stability and favourable pharmacokinetic properties of siRNA. [32][33][34] Several base modifications have been reported but are not yet reached the preclinical and clinical pipeline. Chemical modifications in the sugar ring have been of the most interest to chemists due to their synthetic feasibility and also enhancing multiple drug-like properties.…”

“…Sugar modifications can impact the local conformational dynamics and also the global helical properties of dsRNA; this in turn can contribute to the recognition, binding, and cleavage activity of the proteins involved in RNAi. [32][33][34] Critical reviews that describe the efficacy and stability of the various chemical modifications and conjugative delivery systems in siRNA have been reported. [8][9][10][11][12][32][33][34][35] This review article summarises the basic concepts of sugar puckering, pseudorotation and different stereoelectronic effects operating on the ribose sugar ring.…”

“…[32][33][34] Critical reviews that describe the efficacy and stability of the various chemical modifications and conjugative delivery systems in siRNA have been reported. [8][9][10][11][12][32][33][34][35] This review article summarises the basic concepts of sugar puckering, pseudorotation and different stereoelectronic effects operating on the ribose sugar ring. We have focused on the impact of chemical modifications on the sugar puckering and conformational dynamics of the nucleosides and oligonucleotides.…”