The ups and downs of nucleic acid duplex stability: Structure-stability studies on chemically-modified DNA:RNA duplexes
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TLDR
From results, structure-activity relationships that correlate hybridization affinity with changes in oligonucleotide structure are determined and C-5-substituted pyrimidines stood out as substantially increasing duplex stability.Abstract:
In an effort to discover novel oligonucleotide modifications for antisense therapeutics, we have prepared oligodeoxyribonucleotides containing more than 200 different modifications and measured their affinities for complementary RNA. These include modifications to the heterocyclic bases, the deoxy-ribose sugar and the phosphodiester linkage. From these results, we have been able to determine structure-activity relationships that correlate hybridization affinity with changes in oligonucleotide structure. Data for oligonucleotides containing modified pyrimidine nucleotides are presented. In general, modifications that resulted in the most stable duplexes contained a heteroatom at the 2'-position of the sugar. Other sugar modifications usually led to diminished hybrid stability. Most backbone modifications that led to improved hybridization restricted backbone mobility and resulted in an A-type sugar pucker for the residue 5'to the modified internucleotide linkage. Among the heterocycles, C-5-substituted pyrimidines stood out as substantially increasing duplex stability.read more
Citations
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References
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Journal ArticleDOI
Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide
TL;DR: The results show that the backbone of DNA can be replaced by a polyamide, with the resulting oligomer retaining base-specific hybridization.
Journal ArticleDOI
The molecular theory of polyelectrolyte solutions with applications to the electrostatic properties of polynucleotides.
TL;DR: An analogous situation existed in the field of protein chemistry during the period after the formulation and confirmation of the Debye—Huckel theory of ionic solutions but before Scatchard's incorporation of the theory into his analysis of the binding properties of proteins.
Journal ArticleDOI
PNA hybridizes to complementary oligonucleotides obeying the Watson–Crick hydrogen-bonding rules
Michael Egholm,Ole Buchardt,Leif Christensen,Carsten Behrens,Susan M. Freier,David A. Driver,Rolf H. Berg,Seog K. Kim,Bengt Nordén,Peter E. Nielsen +9 more
TL;DR: It is reported here that PNA containing all four natural nucleobases hybridizes to complementary oligonucleotides obeying the WatsonCrick base-pairing rules, and thus is a true DNA mimic in terms of base- Pair recognition.
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Thermodynamic analysis of ion effects on the binding and conformational equilibria of proteins and nucleic acids: the roles of ion association or release, screening, and ion effects on water activity.
TL;DR: The purpose of this review is to examine the various effects of low- molecular-weight electrolytes on the associations and interactions of proteins and nucleic acids through general electrostatic effects rather than chemical effects of particular ions.
Journal ArticleDOI
Evaluation of 2'-modified oligonucleotides containing 2'-deoxy gaps as antisense inhibitors of gene expression
Brett P. Monia,Elena A. Lesnik,Carolyn Gonzalez,Walt F. Lima,Daniel Peter Claude Mcgee,Charles J. Guinosso,Andrew Mamoro Kawasaki,Phillip Dan Cook,Susan M. Freier +8 more
TL;DR: The use of a previously described 17-mer phosphorothioate for structure-function analysis of 2'-sugar modifications and the results demonstrate the importance of target affinity in the action of antisense oligonucleotides and of RNase H as a mechanism by which these compounds exert their effects.