Background MicroRNAs (miRs) are known to participate in many important biological processes, and their deregulation is highly related to the pathogenesis of many cancers. One of these, microRNA-21, has been shown to play a pivotal role in carcinogenesis by inhibiting tumor suppressor genes in numerous hematologic and solid tumors. Thereby, a significant amount of effort has been contributed to developing a decent therapeutic tool to target oncogenic miR-21 for clinical diagnosis and treatment. One of the promising approaches is based on nucleic acid aptamer selection via the Systematic Evolution of Ligands by EXponential enrichment (SELEX). A major obstacle impeding the aptamer research field is a relatively short circulating half-live in vivo due to nuclease-mediated degradation. The objective of this project is to select a highly structured and stable in biofluids aptamer to target pathogenic miR-21 based on chemically modified L-type nucleic acids (L-NAs). Methods 2'-Fluoro and 2'-methoxy derivatized nucleosides and oligonucleotides were synthesized via organic chemistry approaches. The thermal stability assay, crystal structure determination, human serum degradation assay, and circular dichroism studies were performed to explore the effects of chemical modifications in L-NAs. Results The thermal stability assay and enzymatic assessment reveal that the fluoro-L-oligonucleotides have notable stability. The CD experiment results validate that, the fluoro-modified L-DNA and L-RNA adopt the left-handed helical conformations, which present the mirror-image characteristics of their D-type counterparts. The X-ray crystallographic structural study at the atomic level presents great structural stability of modified L-NAs, as evidenced by the overall and local parameters in the L-helix. Conclusions Combating the miR-21 molecule by the modified L-RNA binder could potentially provide a promising anticancer drug candidate with enhanced stability and low toxicity. More importantly, the developed strategy based on the chemically modified L-NAs could be an advanced tool for targeting other disease-related RNA fragments.

Chemically modified L-nucleic acids for oncogenic microRNA-21 aptamer selection

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