Synthetic strategy targets ‘undruggable’ small RNAs


rna

Molecules can now be designed to target specific small RNAs, opening up a new way to investigate and treat disease © Shutterstock

Chemists in the US have found a way to predict small molecules that can target short pieces of RNA involved in some diseases, such as cancer. The team’s approach has already met with some success, throwing up a molecule that interferes with a microRNA involved in cancer. This opens up the possibility of treating diseases via a target traditionally seen as ‘undruggable’.

MicroRNAs are non-coding lengths of RNA, around 20 nucleotides long, that act as dimmer switches in cells, turning down the output of specific genes. By binding to messenger RNAs, these microRNAs can prevent the production of proteins, leading to a variety of diseases. ‘Pharmaceutical companies traditionally do not pursue RNA as a drug target because they think it’s very difficult to get molecules to be selective,’ explains one of the paper’s authors, Matthew Disney at the Scripps Research Institute. However, by turning traditional drug screening on its head, Disney and colleagues have designed a technique to find small compounds that can selectively target microRNA.

The team used a computational approach they call Inforna, to fold uploaded human microRNA sequences, before hunting for structural motifs in the RNA that would bind to known molecules. With their technique they were able to predict not just lead molecules, but also how selective those molecules would be.

In total, the team identified 27 small molecules that could potentially target folds in microRNAs that would affect their processing. Twelve of these molecules were found to be bioactive, and one was found to stop microRNA-96 from inhibiting production of a protein that causes cell death in cancer cells. ‘In fact [the molecule] was so selective and binding that if we threw it into cancer cells it triggered apoptosis in the cells – causing cancer cells to kill themselves,’ says Disney.

The selectivity of the small molecule found – a benzimidazole – rivalled the RNA recognition of oligonucleotides that bind to it using base pairing. Additionally, the molecule’s small size means it could easily enter and leave cells, making it attractive for drug companies to pursue.

Phillip Zamore, an expert in microRNA at the University of Massachusetts Medical School, US, describes the work as ‘extraordinary’ and sees potential for the technique in helping to understand the role that microRNAs play in cells. Disney agrees: ‘That’s one application of this – to precisely understand what the roles of microRNAs are by using [identified drugs] as probes to knock-off and modulate the function of the RNA.’

The team now hope to identify molecules that can be used to drug other disease-associated RNAs, as well as investigating whether their approach would work in an animal model. ‘A drug has a long path [to the patient] but I think this is solid proof of concept work that people can design small molecule modulators of RNA from sequence and get very selective compounds,’ Disney says.


Related Content

Is there a drug for that?

7 January 2014 In the Pipeline

news image

Derek Lowe ponders whether anything is truly ‘undruggable’ if we look in the right places

Synthetic nanozymes silence hepatitis C

17 July 2012 Research

news image

A new approach to viral diseases uses an artificial nanoparticle complex which can be programmed to shut down viral genes

Most Read

UC Davis chemist sentenced to four years over explosion

19 November 2014 News and Analysis

news image

Postdoc sentenced over attempt to make explosive device and reckless disposal of hazardous waste

Spanish fly

10 October 2013 Podcast | Compounds

news image

Helen Scales looks at cantharidin, the active ingredient in this famous aphrodisiac

Most Commented

Beetle behind breath test for bank notes

17 November 2014 Research

news image

Photonic crystal inks inspired by longhorn beetle could help to fight counterfeiting

Bayer wins race to buy Merck & Co consumer care

9 May 2014 Business

news image

$14bn deal will make Aspirin inventor the number two over-the-counter healthcare company