Small, biologically inert molecules can be converted into bioactive degraders that selectively downregulate disease-causing RNAs. By attaching an RNA molecular recognition element to a second compound that binds to and activates ribonuclease-targeting chimeras (RIBOTACs) to cleave the target, this method turns biologically inactive RNA-binding small molecules into powerful and specific degradation effectors. This research team from the Scripps Research Institute in Jupiter, FL, demonstrated that these RNA degraders provide a means to target the remaining structured regions, which are probably no longer limited to functional regions using the RIBOTAC approach.

The research article, “Programming inactive RNA-binding small molecules into bioactive degrades,” was published in Nature.

RNA’s importance in health and disease biology has been well-documented, creating opportunities for chemical biology to investigate function or intervene against dysfunction in RNA. Since complementary oligonucleotides can bind to and recruit a ribonuclease for cleavage, they are frequently used for sequence-based RNA targeting. This strategy is ideal for focusing on unstructured regions within an RNA because molecular recognition occurs via base pairing.

The biological function of RNA, however, is often determined by the degree of structure it displays. One way in which small molecules can be targeted specifically is by binding to the pockets presented by a particular RNA fold. However, just because a small molecule has taken up residence in an RNA structure does not mean that it will cause a biological reaction.

Xiaohui Liu, Yuquan Tong, and Yeongju Lee hypothesized that in such situations, cleaving the target with a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L1, would be an alternative strategy to modulate RNA biology. When the binding landscape of small molecules was superimposed on RNase L’s substrate specificity, many promising candidate binders were found that could be bioactive after being converted into degraders.

“We discovered around 2,000 new RNA structures that are able to bind drug-like small molecules, and identified six new chemotypes able to bind RNA,” said Matthew D. Disney, PhD, chemist and institute professor of the Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology and the UF Health Cancer Center. “We basically have created an encyclopedia of druggable RNA folds.”

Using Inforna-designed binders as templates, the team developed RIBOTAC degraders that disabled transcriptional and proteomic programs that relied on these oncoproteins for their activity. The study’s proof of concept involved the development of selective degraders for JUN mRNA and MYC mRNA, as well as the pre-microRNA-155 that is linked to disease.

“Our lab tested the efficacy of the RIBOTAC compounds designed to destroy MYC RNA and showed that they effectively kill B-cell lymphomas that are driven by MYC, which are very aggressive and difficult-to-treat tumors,” said John Cleveland, PhD, the executive vice president, center director, and CSO at Moffitt Cancer Center in Tampa. “In sum, these resultsthat one can now design specific RNA degraders to disable many oncogenic RNAs—represents a truly transformative step in anti-cancer therapeutics.”

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