Control the RISC: Toward Nucleic Acid Therapeutics Using Non-Ribose Acyclic-Type Artificial Nucleic Acids

Abstract

In recent years, the development of nucleic acid therapeutics has gained considerable traction, with the aim of controlling the expression of disease-related genes. In particular, numerous small interfering RNA (siRNA) drugs that act through the RNA interference (RNAi) mechanism have been developed. Growing attention has also been directed toward strategies that inhibit microRNAs (miRNAs), which endogenously mediate RNAi. Both approaches involve nucleic acid drugs that modulate the RNA-induced silencing complex (RISC)—the central effector of RNAi—to control disease-related gene expression through either gene silencing or restoration. To improve the design of nucleic acid therapeutics, artificial nucleic acids have been employed to enhance enzymatic stability and target RNA recognition. Although ribose-based artificial nucleic acids have been widely adopted, researchers have also begun exploring alternatives with chemical structures that differ substantially from those of the ribose type, especially to achieve greater enzymatic resistance. Against this backdrop, we have focused on non-ribose type acyclic artificial nucleic acids with amino-acid-based backbones, serinol nucleic acid (SNA) and acyclic L-threoninol nucleic acid (L-aTNA), and have explored their use in designing nucleic acid therapeutics. This account describes designs for both siRNA and antisense oligonucleotides against miRNA (anti-miRNA), which are referred to as AMOs. The unique properties of these acyclic nucleic acids are highlighted, along with an introduction to research on siRNA designs aimed at regulating strand selection during RISC assembly—a key strategy for minimizing off-target effects. This account also includes the design and mechanism of action for our AMO. A key limitation of acyclic artificial nucleic acids is also addressed, with a chemical strategy proposed to overcome it. Ultimately, this review suggests that the unique chemical properties of acyclic artificial nucleic acids may enable the next generation of highly stable and selective nucleic acid therapeutics, paving the way for more effective and safer clinical applications.

Graphical Abstract