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Biochemistry. 2016 Dec 20;55(50):7023-7032. Epub 2016 Dec 5.

Systematic Evaluation of Biophysical and Functional Characteristics of Selenomethylene-Locked Nucleic Acid-Mediated Inhibition of miR-21.

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Academy of Scientific and Innovative Research (AcSIR) , Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India.
CSIR-Institute of Genomics and Integrative Biology , Mathura Road, Delhi 110025, India.
Graduate School of Pharmaceutical Sciences, Osaka University , 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN) , 7-6-8-Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
Graduate School of Pharmaceutical Sciences, Nagoya University , Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan.
Organic Chemistry Division, CSIR-National Chemical Laboratory , Pashan Road, Pune 411008, India.


miRNAs constitute an important layer of gene regulation mediated by sequence-specific targeting of mRNAs. Aberrant expression of miRNAs contributes to a host of pathological states. Promoting cancer, miR-21 is upregulated in variety of cancers and promotes tumor progresion by suppressing a network of tumor suppressor genes. Here we describe a novel class of bicyclic RNA analogues, selenomethylene-locked nucleic acid (SeLNA), that display high affinity, improved metabolic stability, and increased potency for miR-21 inhibition. The thermal stability (Tm) for duplexes was increased significantly with incorporation of SeLNA monomers as compared to that of the unmodified DNA-RNA hybrid. A comprehensive thermodynamic profile obtained by isothermal titration calorimetry revealed a favorable increase in the enthalpy of hybridization for SeLNA containing DNA and target RNA heteroduplexes. SeLNA modifications displayed remarkable binding affinity for miR-21 target RNA with a Ka of ≤1.05 × 108 M-1. We also observed enhanced serum stability for SeLNA-RNA duplexes with a half-life of ≤36 h. These in vitro results were well correlated with the antisense activity in cancer cells imparting up to ∼91% inhibition of miR-21. The functional impact of SeLNA modifications on miR-21 inhibition was further gauged by investigating the migration and invasion characterisitics of cancer cells, which were drastically reduced to ∼49 and ∼55%, respectively, with SeLNA having four such modifications. Our findings demonstrate SeLNA as a promising candidate for therapeutics for disease-associated miRNAs.

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