期刊
BIOCONJUGATE CHEMISTRY
卷 26, 期 6, 页码 1129-1143出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.bioconjchem.5b00193
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资金
- EPSRC [EP/G017905/1]
- SOLVAY
- Russian Science Foundation [14-44-00068]
- Engineering and Physical Sciences Research Council [EP/E003400/1, 1598784] Funding Source: researchfish
- EPSRC [EP/E003400/1] Funding Source: UKRI
- Russian Science Foundation [14-44-00068] Funding Source: Russian Science Foundation
Described here is a new class of peptidyl-oligonucleotide conjugates (POCs) which show efficient cleavage of a target RNA in a sequence-specific manner. Through phosphoramidate attachment of a 17-mer T Psi C-targeting oligonucleotide to amphiphilic peptide sequences containing leucine, arginine, and glycine, zero-linker conjugates are created which exhibit targeted phosphodiester cleavage under physiological conditions. tRNA(Phe) from brewer's yeast was used as a model target sequence in order to probe different structural variants of POCs in terms of selective T Psi C-arm directed cleavage. Almost quantitative (97-100%) sequence-specific tRNA cleavage is observed for several POCs over a 24 h period with a reaction half-life of less than 1 h. Nontargeted cleavage of tRNA(Phe) or HIV-1 RNA is absent. Structure-activity relationships reveal that removal of the peptide's central glycine residue significantly decreases tRNA cleavage activity; however, this can be entirely restored through replacement of the peptide's C-terminal carboxylic acid group with the carboxamide functionality. Truncation of the catalytic peptide also has a detrimental effect on POC activity. Based on the encouraging results presented, POCs could be further developed with the aim of creating useful tools for molecular biology or novel therapeutics targeting specific messenger, miRNA, and genomic viral RNA sequences.
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