Document Detail


Induction of RNase H activity by Arabinose-peptide nucleic acid chimeras.
MedLine Citation:
PMID:  17373768     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We report the syntheses of chimeras of peptide nucleic acid (PNA) with DNA and 2'-deoxy 2'-fluoroarabinonucleic acid (2'-FANA). Chimeric oligomers possessing a single central PNA insert were capable of forming hybrid duplexes with complementary RNA, although with diminished thermal stability in comparison to the unmodified oligomers. We subsequently determined the ability of the DNA and 2'-FANA oligomers of mixed-base composition to elicit human RNase H1 degradation of complementary RNA that was either unstructured or as a hairpin. In the case of the more rigid FANA strand, a PNA insert led to a higher ability of the chimera to direct the degradation of both types of RNA targets. Generally, the enhancement observed was greater for a butanediol linker than for a more rigid PNA linker. Along with previous work, these studies suggest that the general flexibility associated with an acyclic insert (e.g., butyl vs PNA)--and not necessarily the presence of local structural imperfections in the heteroduplex--is beneficial for RNase H1 activity. As well, there are implications to the charge nature of non-nucleotide inserts (neutral vs negative) and their ability to maintain RNase H activity that may serve to direct further design considerations. Together, these studies support the notion that flexibility of antisense oligonucleotide (AON)/RNA hybrids is essential for high RNase H catalysis, in which an enzyme-induced altered trajectory of the bound AON/RNA substrate could facilitate optimal interaction with the catalytic site of RNase H.
Authors:
Bénédicte M Pâtureau; Robert H E Hudson; Masad J Damha
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Bioconjugate chemistry     Volume:  18     ISSN:  1043-1802     ISO Abbreviation:  Bioconjug. Chem.     Publication Date:    2007 Mar-Apr
Date Detail:
Created Date:  2007-03-21     Completed Date:  2007-05-03     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9010319     Medline TA:  Bioconjug Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  421-30     Citation Subset:  IM    
Affiliation:
Department of Chemistry, McGill University, Montreal, Quebec, Canada.
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MeSH Terms
Descriptor/Qualifier:
Arabinose / chemical synthesis,  chemistry,  pharmacology*
DNA / chemistry,  pharmacology
Genes, ras / physiology*
Humans
Nucleic Acid Conformation
Nucleic Acid Heteroduplexes
Oligonucleotides, Antisense / chemistry,  pharmacology*
Peptide Nucleic Acids / chemical synthesis,  chemistry,  pharmacology*
Ribonuclease H / chemistry,  metabolism*
Chemical
Reg. No./Substance:
0/Nucleic Acid Heteroduplexes; 0/Oligonucleotides, Antisense; 0/Peptide Nucleic Acids; 147-81-9/Arabinose; 9007-49-2/DNA; EC 3.1.26.4/Ribonuclease H

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


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