CHAPTER 13: MicroRNA-specific Argonaute 2 Protein Inhibitors and AGO Loading Inhibitors

Small non-coding microRNAs (miRNAs) are involved in virtually all physiological processes and deregulated in many human diseases. They exert their gene silencing function through association with Argonaute (AGO) proteins in the RNA-induced silencing complex (RISC). AGO proteins have been found to be deregulated in human diseases, including cancer, and are thus analogous to miRNAs as attractive therapeutic targets. The best known and most successful miRNA therapeutic, miravirsen, which was successfully evaluated in phase 2 clinical trials for the treatment of hepatitis C virus (HCV) infection, is a specific miR-122 inhibitor with a dual function of blocking AGO2 inhibition, supporting the potential of AGO-based therapeutics for the treatment of human diseases. This chapter first discusses the miRNA biogenesis process and the Argonaute family of proteins (AGO). Next, the mechanisms of AGO-mediated gene silencing are explained. The final section describes miRNA-based therapeutics, where we focus on therapeutic strategies of targeting AGO proteins for the treatment of human diseases, with an emphasis on cancer.