Altering the Cleaving Effector in Chimeric Molecules that Target RNA Enhances Cellular Selectivity.
Blessy M SureshYuquan TongDaniel AbeggAlexander AdibekianJessica L Childs-DisneyMatthew D DisneyPublished in: ACS chemical biology (2023)
Small molecules that target RNA and effect their cleavage are useful chemical probes and potential lead medicines. In this study, we investigate factors affecting degradation of two cancer-associated RNA targets, the mRNA that encodes the transcription factor JUN (c-Jun) and the hairpin precursor to microRNA-372 (pre-miR-372). The two RNA targets harbor the same small-molecule binding site juxtaposed with different neighboring structures. Specifically, pre-miR-372 has AU pairs and contiguous purines on one strand near the small-molecule binding site, making it an ideal substrate for oxidative cleavage via the direct degrader bleomycin A5. In contrast, while JUN mRNA has a similar number of AU pairs near the small-molecule binding site, it lacks contiguous purine nucleotides. Instead, it contains unpaired pyrimidine nucleotides, which are preferred substrates for RNase L, a ribonuclease that can be recruited to RNA with heterobifunctional ribonuclease targeting chimeras (RiboTACs). We hypothesized that structural features surrounding the binding site could be leveraged to program selective small-molecule degradation by alteration of the cleaving module. Indeed, the bleomycin degrader cleaves pre-miR-372 in gastric cancer cells but not JUN mRNA. Conversely, the RiboTAC cleaves JUN mRNA but not pre-miR-372. Thus, the selection of the appropriate cleaving effector moiety for an RNA-binding small molecule can be leveraged to cleave an RNA selectively in a predictable manner, which could have broad implications.
Keyphrases
- small molecule
- cell proliferation
- protein protein
- long non coding rna
- long noncoding rna
- nucleic acid
- transcription factor
- dna binding
- binding protein
- computed tomography
- magnetic resonance imaging
- regulatory t cells
- cell therapy
- immune response
- drug delivery
- gold nanoparticles
- amino acid
- single molecule
- quality improvement
- human health