Inhibiting microRNAs for targeted drug therapy Regulators of gene transcription and protein expression have immense potential in targeted drug therapy applications. Scientists developed potent inhibitors of a molecule in one class of regulators that plays a role in numerous disease processes. Health © Thinkstock The cellular pathways and chain of events from gene to protein are complicated. However, one family of short RNA molecules called microRNAs are implicated in the disease process for diabetes, neurological disorders and cancer. MicroRNAs regulate gene expression post-transcriptionally — after transcription where the genetic code is passed from a DNA template to messenger RNA (mRNA). They effectively silence gene expression by preventing translation of the mRNA template into the sequence codes required for protein production. Chemically engineered molecules have been shown to inhibit microRNAs but do not have the appropriate pharmacokinetic properties for targeted therapy. Scientists investigated a specialised family of RNA-binding proteins (Argonaute) that mediate the microRNA silencing processes with EU funding of the MICRORNA FBDD project. Recent evidence demonstrated that the Argonaute 2 protein regulates microRNA. Argonaute 2 binds to the microRNA's 'seed region', facilitating binding of the complex to mRNA to block translation and silence gene expression. Scientists developed novel microRNA-specific Argonaute 2-inhibitors that bind first to the microRNA seed region and then to the active site of the Argonaute 2 protein. This active site binding for protein-inhibition technique opens up novel avenues for development of targeted drug therapy that was not possible with engineered inhibitor molecules. Using their model for rational drug design, the researchers synthesised inhibitors targeting microRNA-122, which plays a role in hepatitis C infection. The inhibitors were very effective at preventing binding of the natural ligand at low concentration. The search is now on for highly specific inhibitors for therapeutic use. MICRORNA FBDD developed a novel family of microRNA inhibitors that are much more effective and possess the pharmacokinetics appropriate for targeted drug therapy. The techniques for rational design will facilitate the rapid development of microRNA-inhibiting drugs for treating several diseases to benefit the EU economy and its citizens.