Drug Discovery Perspectives of Antisense Oligonucleotides

The era of innovative RNA therapies using antisense oligonucleotides (ASOs), siRNAs, and mRNAs is beginning. Since the emergence of the concept of ASOs in 1978, it took more than 20 years before they were developed into drugs for commercial use. Nine ASO drugs have been approved to date. However, they target only rare genetic diseases, and the number of chemistries and mechanisms of action of ASOs are limited. Nevertheless, ASOs are accepted as a powerful modality for next-generation medicines as they can theoretically target all disease-related RNAs, including (undruggable) protein-coding RNAs and non-coding RNAs. In addition, ASOs can not only downregulate but also upregulate gene expression through diverse mechanisms of action. This review summarizes the achievements in medicinal chemistry that enabled the translation of the ASO concept into real drugs, the molecular mechanisms of action of ASOs, the structure-activity relationship of ASO-protein binding, and the pharmacology, pharmacokinetics, and toxicology of ASOs. In addition, it discusses recent advances in medicinal chemistry in improving the therapeutic potential of ASOs by reducing their toxicity and enhancing their cellular uptake.