Document Detail


RNA targeting with peptide conjugates of oligonucleotides, siRNA and PNA.
MedLine Citation:
PMID:  17113327     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Towards the development of oligonucleotide analogues and siRNA as drugs, one potential alternative to the use of liposomal transfection agents is the covalent conjugation of a cell-penetrating peptide (CPP), with the intention of imparting on the oligonucleotide or siRNA an enhanced ability to enter mammalian cells and reach the appropriate RNA target. We have developed robust methods for the chemical synthesis of disulfide-linked conjugates of oligonucleotide analogues, siRNA and peptide nucleic acids (PNA) with a range of cationic and other CPPs. In a HeLa cell assay with integrated plasmid reporters of Tat-dependent trans-activation at the TAR RNA target in the cell nucleus, we were unable to obtain steric block inhibition of gene expression for conjugates of CPPs with a 12-mer oligonucleotide mixmer of 2'-O-methyl and locked nucleic acids units. By contrast, we were able to obtain some reductions in expression of P38alpha MAP kinase mRNA in HeLa cells using microM concentrations of Penetratin or Tat peptides conjugated to the 3'-end of the sense strand of siRNA. However, the most promising results to date have been with a 16-mer PNA conjugated to the CPP Transportan or a double CPP R(6)-Penetratin, where we have demonstrated Tat-dependent trans-activation inhibition in HeLa cells. Results to date suggest the possibility of development of CPP-PNA conjugates as anti-HIV agents as well as other potential applications involving nuclear cell delivery, such as the redirection of splicing.
Authors:
John J Turner; Simon Jones; Martin M Fabani; Gabriela Ivanova; Andrey A Arzumanov; Michael J Gait
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review     Date:  2006-11-17
Journal Detail:
Title:  Blood cells, molecules & diseases     Volume:  38     ISSN:  1079-9796     ISO Abbreviation:  Blood Cells Mol. Dis.     Publication Date:    2007 Jan-Feb
Date Detail:
Created Date:  2006-12-26     Completed Date:  2007-10-05     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  9509932     Medline TA:  Blood Cells Mol Dis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Humans
Peptide Nucleic Acids*
Peptides*
RNA / metabolism*
RNA, Small Interfering*
Grant Support
ID/Acronym/Agency:
MC_U105178803//Medical Research Council
Chemical
Reg. No./Substance:
0/Peptide Nucleic Acids; 0/Peptides; 0/RNA, Small Interfering; 63231-63-0/RNA

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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