Chemistry of Therapeutic Oligonucleotides That Drives Interactions with Biomolecules

Abstract

Oligonucleotide therapeutics that can modulate gene expression have been gradually developed for clinical applications over several decades. However, rapid advances have been made in recent years. Artificial nucleic acid technology has overcome many challenges, such as (1) poor target affinity and selectivity, (2) low in vivo stability, and (3) classical side effects, such as immune responses; thus, its application in a wide range of disorders has been extensively examined. However, even highly optimized oligonucleotides exhibit side effects, which limits the general use of this class of agents. In this review, we discuss the physicochemical characteristics that aid interactions between drugs and molecules that belong to living organisms. By systematically organizing the related data, we hope to explore avenues for symbiotic engineering of oligonucleotide therapeutics that will result in more effective and safer drugs.

Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry

“…A more scientifically grounded approach, aimed at concurrently and effectively curtailing non-specific interactions with RNA and proteins, may be prefered in addressing these toxicity challenges. Yet, to the best of our knowledge, no such strategy have been proposed 29 , 30 .…”

Recent Advancements in Development and Therapeutic Applications of Genome-Targeting Triplex-Forming Oligonucleotides and Peptide Nucleic Acids

“…Our group recently described the physicochemical properties of therapeutic oligonucleotide [1] and DDS technologies [2] from a symbiotic perspective. Currently, these factors are considered for RNA-targeting therapeutic oligonucleotides such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs).…”

“…Combined with emerging drug delivery system (DDS) technologies, therapeutic oligonucleotides are recently attracting increasing attention as new drug modalities. We recently summarized the physicochemical properties of these artificial modifications (ASOs and siRNAs) [1] and DDS technologies based on material symbiosis [2]. Messenger RNAs (mRNAs) are the target genes of these ASOs and siRNAs, and decreasing the number of disease-associated mRNAs can result in symptom relief, improved function, and prolonged survival for patients.…”

“…Thus, the development of more symbiotic and facile methods is desirable. In this context, triplex-forming oligonucleotides (TFOs) and peptide nucleic acids (PNAs) exhibit significant potential as genome-targeting tools [7,8], considering that those aforementioned ASO and DDS modification methods [1,2] are also applicable to TFOs and PNAs. Both TFOs and PNA can bind to a DNA duplex in a sequence-specific manner (Figure 1), which enables the modulation of the target DNA functions (the structural features of TFOs and PNA are described in the following sections).…”

Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry

“…[24][25][26][27] However, some recent clinical failures of the highly optimized ASOs with state-of-the-art strategies, including Vupanorsen 28 and ALG-020572 29 , have revealed that these approaches are insufficient to appease the toxic aspect of the current form of ASOs. 30,31 In this context, as the two off-target pathways are thought to be intertwined and inseparably contribute to the class toxicity, 13 the concurrent suppression of both off-target interactions is expected to be key to overcoming this toxicity challenge. However, none of the previous approaches supports the simultaneous suppression of these two toxicity pathways.…”