Small Drugs, Huge Impact: The Extraordinary Impact of Antisense Oligonucleotides in Research and Drug Development

Abstract

Antisense oligonucleotides (ASOs) are an increasingly represented class of drugs. These small sequences of nucleotides are designed to precisely target other oligonucleotides, usually RNA species, and are modified to protect them from degradation by nucleases. Their specificity is due to their sequence, so it is possible to target any RNA sequence that is already known. These molecules are very versatile and adaptable given that their sequence and chemistry can be custom manufactured. Based on the chemistry being used, their activity may significantly change and their effects on cell function and phenotypes can differ dramatically. While some will cause the target RNA to decay, others will only bind to the target and act as a steric blocker. Their incredible versatility is the key to manipulating several aspects of nucleic acid function as well as their process, and alter the transcriptome profile of a specific cell type or tissue. For example, they can be used to modify splicing or mask specific sites on a target. The entire design rather than just the sequence is essential to ensuring the specificity of the ASO to its target. Thus, it is vitally important to ensure that the complete process of drug design and testing is taken into account. ASOs’ adaptability is a considerable advantage, and over the past decades has allowed multiple new drugs to be approved. This, in turn, has had a significant and positive impact on patient lives. Given current challenges presented by the COVID-19 pandemic, it is necessary to find new therapeutic strategies that would complement the vaccination efforts being used across the globe. ASOs may be a very powerful tool that can be used to target the virus RNA and provide a therapeutic paradigm. The proof of the efficacy of ASOs as an anti-viral agent is long-standing, yet no molecule currently has FDA approval. The emergence and widespread use of RNA vaccines during this health crisis might provide an ideal opportunity to develop the first anti-viral ASOs on the market. In this review, we describe the story of ASOs, the different characteristics of their chemistry, and how their characteristics translate into research and as a clinical tool.

Mini Review Therapeutic Strategies Targeting for Biofilm and Bone Infections

“…RNA interference (RNAi) is effectiveness in transcriptive level as a novel administration. For bacterial elimination, antisense RNA can recruit RNase to degrade base-paired mRNA and repel RNA polymerase to block translation ( Quemener et al, 2022 ). Similarly, miRNA and siRNA can form RNA-induced silencing complex intraocularly for eukaryote, which are enable to modulate bone homeostasis ( Jinek and Doudna, 2009 ).…”

“…Depending on DNA/RNA heteroduplex formation, RNA cleavage is induced by RNase, and the mRNA expression level is ultimately modulated. ASOs are highly valuable as a novel strategy to treat a wide range of diseases linked to dysregulated gene expression ( Quemener et al, 2022 ). The two-component regulatory system (TCS) commonly comprises two components termed “the sensor kinase” and “the response regulator.” TCSs are ubiquitous in bacteria but rare in mammalian cells.…”

“…Considering the stability of ASOs in biological fluids, many improvements have been introduced to increase resistance against nucleases. Peptide nucleic acid (PNA) molecules are the third generation of ASOs ( Quemener et al, 2022 ). They consist of a chain of N-(2-aminoethyl) glycine units, and the nucleobases can attach to N-(2-aminoethyl) glycine units via a methyl carbonyl linker ( Larsen et al, 1999 ).…”

Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs

“…The phosphorothioate modification of the backbone greatly improved the binding of the oligonucleotides to the plasma proteins, increasing the time of the oligonucleotides in the circulation, while reducing their elimination. In vivo stability and resistance to degradation by DNases or RNases have been greatly improved by the different chemical modifications introduced in the nucleotides and in the backbone [ 130 , 131 ]. Regarding the delivery to the target cells, oligonucleotides are hydrophilic molecules and cannot passively cross the plasma membrane in the same way as the small molecule lipophilic drugs.…”

“…Finally, the third generation ASOs shows the most enhanced resistance against nucleases and the best target affinity, compared to the previous generations [ 144 , 145 , 146 ]. The last generation is also potentially considered the most safe, thanks to its high specificity, affinity, and very limited off-target effects that can be avoided with many bioinformatic tools [ 131 ]. Thus, the chemical modification introduced into DNA or RNA oligonucleotides ( Figure 2 ) have allowed an improvement in the specificity, stability, safety and pharmacokinetic/pharmacodynamic profiles, making this class of compounds more reliable for clinical purposes [ 131 , 144 ].…”