5:00 PM
Apr 19, 2018
 |  BC Innovations  |  Tools & Techniques

Structured outlook

RNA drug developers get a boost from mass discovery of functional mRNA structure

A Cell study capturing hundreds of E. coli mRNA structures makes the case that complex, functionally relevant RNA structures are the rule, not the exception, and builds confidence that mRNAs -- once widely considered undruggable -- could furnish a broad reservoir of new targets. The question is whether the study’s findings will extend to mammalian cells.

For years, the prevailing assumption was that the only key information in mRNA lies in its primary structure -- the linear sequence that dictates the proteins it encodes; the three-dimensional structures of mRNAs were not thought to be important for their functional roles.

The new findings, from a group led by Ribometrix Inc. founder Kevin Weeks, showed that most mRNAs in E. coli are in fact highly structured, and those structures control the rates at which mRNAs are translated. The group found that almost all of the 400 mRNA structures profiled controlled the efficiency of translating mRNA into proteins by modulating ribosome binding, among other processes.

Weeks is a professor of chemistry at University of North Carolina at Chapel Hill. His spinout Ribometrix is one of a spate of companies formed in the last few years to develop small molecule therapeutics that bind RNA.

According to Weeks, there has been increasing recognition that mRNA can form complex structures, but detailed observations have been limited to specific transcripts. This study’s scale allowed far more extensive conclusions to be drawn.

“The big surprise was that for every single RNA we looked at, it’s reasonable to postulate that their function is regulated in some way by RNA structure,” said Weeks.

He added that the study “came down authoritatively on some long-standing controversies” about how much structure RNAs have, and whether it matters for function. “The conclusion of this study is that the structures are common, and that a lot of structures that you find clearly do matter.”

“The big surprise was that for every single RNA we looked at, it’s reasonable to postulate that their function is regulated in some way by RNA structure.”

Kevin Weeks, UNC Chapel Hill

Anthony Mustoe, an author of the study and postdoctoral fellow in Weeks’ lab, said the study suggests translational researchers will find plenty of footholds in RNA targets. “The biggest take-home message is there’s most likely structure there; you just need good data to see it.”

The study was co-authored by Razvan Nutiu and colleagues from the Novartis Institutes for BioMedical Research (NIBR), who told BioCentury the results provide large-scale evidence that the structures of RNAs have biological functions.

Nutiu said Novartis AG is investing in RNA-targeting therapeutics. It has branaplam (LMI070), a small molecule that stabilizes a structure formed by the SMN2 pre-mRNA and a ribonucleic protein complex, in Phase I/II testing to treat spinal muscular atrophy (SMA). He declined to disclose details of other...

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