Oligonucleotide therapeutics are medicines composed of nucleotides, the building blocks of DNA and RNA. siRNA (small interfering RNA) therapeutics are one type of oligonucleotide therapeutics. They exert their pharmacological effects by selectively degrading target mRNA, which serves as the blueprint for the production of target proteins.
siRNAs can be designed using software based on the sequence information of target mRNAs. The subsequent optimization process required to develop siRNAs into drug candidates can also be carried out efficiently using standardized approaches. In addition, siRNAs share many fundamental properties as medicines regardless of their targets, allowing for a high degree of predictability in their pharmacokinetics and safety profiles.
Small-molecule and antibody therapeutics can act only on a subset of the proteins found in the human body. In principle, however, siRNAs can target the mRNAs encoding virtually any protein. This ability to address a much broader range of target molecules is one of the major advantages of siRNA therapeutics and has the potential to greatly expand the universe of druggable targets.
siRNAs consist of two short oligonucleotide strands. Inside cells, an siRNA is incorporated into a protein called AGO2 (Argonaute 2) to form a complex known as RISC (RNA-induced silencing complex). The RISC complex specifically binds to and cleaves the target mRNA, thereby suppressing the expression of the corresponding target protein.
Small-molecule and antibody therapeutics can act only on proteins with specific structural features (yellow proteins for small-molecule therapeutics and pink proteins for antibody therapeutics). In contrast, siRNA therapeutics can act on virtually any type of mRNA (yellow-green), irrespective of the structure of the encoded protein. This enables siRNA therapeutics to address target molecules that are difficult or impossible to modulate with small-molecule or antibody therapeutics (blue, purple, and green proteins), thereby substantially expanding the range of potential drug targets.