Tetrazine-Induced Bioorthogonal Activation of Vitamin E-Modified siRNA for Gene Silencing. 2022

Xueli Zhang, and Amu Gubu, and Jianfei Xu, and Ning Yan, and Wenbo Su, and Di Feng, and Qian Wang, and Xinjing Tang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences and Chemical Biology Center, Peking University, No. 38 Xueyuan Rd., Beijing 100191, China.

The temporal activation of siRNA provides a valuable strategy for the regulation of siRNA activity and conditional gene silencing. The bioorthogonal bond-cleavage reaction of benzonorbonadiene and tetrazine is a promising trigger in siRNA temporal activation. Here, we developed a new method for the bio-orthogonal chemical activation of siRNA based on the tetrazine-induced bond-cleavage reaction. Small-molecule activatable caged siRNAs were developed with the 5'-vitamin E-benzonobonadiene-modified antisense strand targeting the green fluorescent protein (GFP) gene and the mitotic kinesin-5 (Eg5) gene. The addition of tetrazine triggered the reaction with benzonobonadiene linker and induced the linker cleavage to release the active siRNA. Additionally, the conditional gene silencing of both exogenous GFP and endogenous Eg5 genes was successfully achieved with 5'-vitamin E-benzonobonadiene-caged siRNAs, which provides a new uncaging strategy with small molecules.

UI MeSH Term Description Entries
D014810 Vitamin E A generic descriptor for all TOCOPHEROLS and TOCOTRIENOLS that exhibit ALPHA-TOCOPHEROL activity. By virtue of the phenolic hydrogen on the 2H-1-benzopyran-6-ol nucleus, these compounds exhibit varying degree of antioxidant activity, depending on the site and number of methyl groups and the type of ISOPRENOIDS.
D016547 Kinesins A family of microtubule-associated mechanical adenosine triphosphatases, that uses the energy of ATP hydrolysis to move organelles along microtubules including mitosis, meiosis, and axonal transport. Kinesin,Kinesin Heavy-Chain Protein,Kinesin Light-Chain Protein,Kinesin Light-Chain Proteins,Kinesin Superfamily,Heavy-Chain Protein, Kinesin,Light-Chain Protein, Kinesin,Light-Chain Proteins, Kinesin,Protein, Kinesin Heavy-Chain,Protein, Kinesin Light-Chain,Proteins, Kinesin Light-Chain,Superfamily, Kinesin
D049452 Green Fluorescent Proteins Protein analogs and derivatives of the Aequorea victoria green fluorescent protein that emit light (FLUORESCENCE) when excited with ULTRAVIOLET RAYS. They are used in REPORTER GENES in doing GENETIC TECHNIQUES. Numerous mutants have been made to emit other colors or be sensitive to pH. Green Fluorescent Protein,Green-Fluorescent Protein,Green-Fluorescent Proteins,Fluorescent Protein, Green,Fluorescent Proteins, Green,Protein, Green Fluorescent,Protein, Green-Fluorescent,Proteins, Green Fluorescent,Proteins, Green-Fluorescent
D020868 Gene Silencing Interruption or suppression of the expression of a gene at transcriptional or translational levels. Gene Inactivation,Inactivation, Gene,Silencing, Gene
D034741 RNA, Small Interfering Small double-stranded, non-protein coding RNAs (21-31 nucleotides) involved in GENE SILENCING functions, especially RNA INTERFERENCE (RNAi). Endogenously, siRNAs are generated from dsRNAs (RNA, DOUBLE-STRANDED) by the same ribonuclease, Dicer, that generates miRNAs (MICRORNAS). The perfect match of the siRNAs' antisense strand to their target RNAs mediates RNAi by siRNA-guided RNA cleavage. siRNAs fall into different classes including trans-acting siRNA (tasiRNA), repeat-associated RNA (rasiRNA), small-scan RNA (scnRNA), and Piwi protein-interacting RNA (piRNA) and have different specific gene silencing functions. RNA, Scan,Repeat-Associated siRNA,Scan RNA,Small Scan RNA,Trans-Acting siRNA,siRNA,siRNA, Repeat-Associated,siRNA, Trans-Acting,Short Hairpin RNA,Short Interfering RNA,Small Hairpin RNA,Small Interfering RNA,scnRNA,shRNA,tasiRNA,Hairpin RNA, Short,Hairpin RNA, Small,Interfering RNA, Short,Interfering RNA, Small,RNA, Short Hairpin,RNA, Short Interfering,RNA, Small Hairpin,RNA, Small Scan,Repeat Associated siRNA,Scan RNA, Small,Trans Acting siRNA,siRNA, Repeat Associated,siRNA, Trans Acting

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