Targeting the miRNA pathway with small-molecule modulators of Argonaute protein

The deregulation of miRNAs expression and activity is associated with a variety of human pathologies, especially hematological malignancies. Because targeting miRNA expression can modify the disease phenotype, the understanding of the role of miRNAs in pathological processes is currently spurring the development of specific oligonucleotides or plasmid- and virus-based constructs able to modulate miRNA levels. In this context, the usage small-molecules may constitute an improved strategy to circumvent problems of delivery and immunogenic response as well as a very attractive way to devise new therapeutic tools. Here we present a new lead-like modulator of Argonaute 2 (Ago2) protein, which is a component of the RNA-induced silencing complex (RISC) with a central role in RNA silencing. We show that a specific small-molecule is able to interfere with the miRNAs-loading into the Ago2 complex and that the disruption of this binding results in an improvement of the differentiation capability