Modified Nucleic Acids: Expanding the Capabilities of Functional Oligonucleotides

Abstract

In the last three decades, oligonucleotides have been extensively investigated as probes, molecular ligands and even catalysts within therapeutic and diagnostic applications. The narrow chemical repertoire of natural nucleic acids, however, imposes restrictions on the functional scope of oligonucleotides. Initial efforts to overcome this deficiency in chemical diversity included conservative modifications to the sugar-phosphate backbone or the pendant base groups and resulted in enhanced in vivo performance. More importantly, later work involving other modifications led to the realization of new functional characteristics beyond initial intended therapeutic and diagnostic prospects. These results have inspired the exploration of increasingly exotic chemistries highly divergent from the canonical nucleic acid chemical structure that possess unnatural physiochemical properties. In this review, the authors highlight recent developments in modified oligonucleotides and the thrust towards designing novel nucleic acid-based ligands and catalysts with specifically engineered functions inaccessible to natural oligonucleotides.

Terminal Mono- and Bis-Conjugates of Oligonucleotides with Closo-Dodecaborate: Synthesis and Physico-Chemical Properties

“…Oligonucleotides and their modified analogs are widely used as a basis for the development of antisense agents for targeted gene therapy of different diseases [ 17 , 18 , 19 ]. From this point of view, it was interesting to examine the ability of oligonucleotides with terminal boron clusters to form complementary complexes with the RNA target ( RT ).…”

“…We, therefore, carried out thermal melting studies for the hybrid duplexes of RNA with DNA (D), 2′-O-methyl RNA (M), and 2′-fluoro modified RNA (RF) oligomers and their conjugates with closo-dodecaborates (Table 2, Figure 7). Oligonucleotides and their modified analogs are widely used as a basis for the development of antisense agents for targeted gene therapy of different diseases [17][18][19]. From this point of view, it was interesting to examine the ability of oligonucleotides with terminal boron clusters to form complementary complexes with the RNA target (RT).…”

The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery

“…An example of nucleobase modifications is the methylation of 5′ cytosines. This increases the hydrophobicity of ASOs, thereby enhancing their affinity to target RNA [ 76 , 77 ]. This modification has been implemented for the improvement of a Superoxide Dismutase 1-targeting ASO currently in clinical trial for the treatment of amyotrophic lateral sclerosis [ 78 , 79 ].…”

The Potential of Induced Pluripotent Stem Cells to Test Gene Therapy Approaches for Neuromuscular and Motor Neuron Disorders

“…ASOs are synthetic single-stranded strings of nucleic acids that bind to RNA through standard Watson-Crick base pairing. After binding to the targeted RNA, the antisense drug can modulate the function of the targeted RNA by several mechanisms (Bennett and Swayze, 2010;Crooke et al, 2018), depending on the chemical modifications and the binding position on the target RNA (Wurster and Ludolph, 2018;Talbot and Wood, 2019;Ochoa and Milam, 2020). Briefly, ASOs can promote degradation of the targeted RNA, by mimicking DNA-RNA pairing and activating endogenous nucleases (i.e., RNase H1), or can modulate the processing of the RNA molecule, without inducing its degradation.…”