Peptidyl鈥揙ligonucleotide Conjugates Demonstrate Efficient Cleavage of RNA in a Sequence-Specific Manner

详细信息    查看全文

• 作者：Aled Williams ; Yaroslav Staroseletz ; Marina A. Zenkova ; Laurent Jeannin ; Harmesh Aojula ; Elena V. Bichenkova
• 刊名：Bioconjugate Chemistry
• 出版年：2015
• 出版时间：June 17, 2015
• 年：2015
• 卷：26
• 期：6
• 页码：1129-1143
• 全文大小：602K
• ISSN：1520-4812

文摘

Described here is a new class of peptidyl鈥搊ligonucleotide conjugates (POCs) which show efficient cleavage of a target RNA in a sequence-specific manner. Through phosphoramidate attachment of a 17-mer T唯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鈥檚 yeast was used as a model target sequence in order to probe different structural variants of POCs in terms of selective T唯C-arm directed cleavage. Almost quantitative (97鈥?00%) 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鈥揳ctivity relationships reveal that removal of the peptide鈥檚 central glycine residue significantly decreases tRNA cleavage activity; however, this can be entirely restored through replacement of the peptide鈥檚 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.