Researchers from the University of Cambridge last month reported on the development of novel microRNA inhibitors they hope can be developed into a new class of therapeutic capable of knocking down the small, non-coding RNAs in a variety of tissues.
At this stage, however, the molecules have only been tested in vitro against a single miRNA, with future optimization and testing contingent on the investigators securing new grant funding for their work.
According to Marco Schmidt, a researcher in the lab of University of Cambridge professor Chris Abell and lead author of the study, the work stems from the recognition that while miRNAs can be effectively suppressed by antisense agents such as locked nucleic acids, these molecules are too large to easily cross cell membranes and are not easily targeted to specific cell types.
For example, Santaris Pharma’s LNA-based miRNA-122 inhibitor miravirsen, which is in phase II testing as a treatment for hepatitis C, shows the potential of miRNA-targeting drugs, but is an “exception in microRNA drug discovery,” the investigators wrote in a paper appearing in ACS Chemical Biology.
“The only reason miravirsen is effective is because of the phosphorothioate modification that enables it to accumulate in the liver where its target is exclusively expressed,” Schmidt told Gene Silencing News. “The problem is how to target other microRNAs in other tissues.”
To overcome this issue, the Cambridge team aimed to create a class of miRNA inhibitors that bind to both a miRNA’s seed region and the active site of Argonaute 2.
By combining these two inhibitory properties, the “mixed inhibitor … would benefit from cooperative binding,” and would have a lower molecular weight and be more hydrophobic than standard antisense molecules, they noted in their paper.
The scientists developed a drug-design model that enabled them to identify Ago2 active site binders that could be linked to a peptide nucleic acid sequence against miR-122 — a miRNA they selected due to its high profile in the field.
In in vitro testing, these molecules had an IC50 of 100 nM, “giving evidence that the strategy has potential for inhibition of microRNA functions,” the paper states.
Schmidt stressed that his work is still very preliminary, and said that he is currently pursuing additional funding in order to further optimize the inhibitors, and to test them in vivo against additional miRNAs.