Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogues.

Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogues. Research Abstract Details 

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Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogues. Abstract Text:

Rekha Pattanayek,Latsavongsakda Sethaphong,Chongle Pan,Marija Prhavc,Thazha P Prakash,Muthiah Manoharan,Martin Egli,

Chemical modification of nucleic acids at the 2'-position of ribose has generated antisense oligonucleotides (AONs) with a range of desirable properties. Electron-withdrawing substituents such as 2'-O-[2-(methoxy)ethyl] (MOE) confer enhanced RNA affinity relative to that of DNA by conformationally preorganizing an AON for pairing with the RNA target and by improving backbone hydration. 2'-Substitution of the ribose has also been shown to increase nuclease resistance and cellular uptake via changes in lipophilicity. Interestingly, incorporation of either 2'-O-[2-(methylamino)-2-oxoethyl]- (NMA) or 2'-O-(N-methylcarbamate)-modified (NMC) residues into AONs has divergent effects on RNA affinity. Incorporation of 2'-O-NMA-T considerably improves RNA affinity while incorporation of 2'-O-NMC-T drastically reduces RNA affinity. Crystal structures at high resolution of A-form DNA duplexes containing either 2'-O-NMA-T or 2'-O-NMC-T shed light on the structural origins of the surprisingly large difference in stability given the relatively minor difference in chemistry between NMA and NMC. NMA substituents adopt an extended conformation and use either their carbonyl oxygen or amino nitrogen to trap water molecules between phosphate group and sugar. The conformational properties of NMA and the observed hydration patterns are reminiscent of those found in the structures of 2'-O-MOE-modified RNA. Conversely, the carbonyl oxygen of NMC and O2 of T are in close contact, providing evidence that an unfavorable electrostatic interaction and the absence of a stable water structure are the main reasons for the loss in thermodynamic stability as a result of incorporation of 2'-O-NMC-modified residues.

Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogues. Publishing Authors By Initials

R Pattanayek,L Sethaphong,C Pan,M Prhavc,TP Prakash,M Manoharan,M Egli,

For similar heterocyclic compounds: heterocyclic compounds, 1-ring: pyrimidines: pyrimidine nucleosides: thymidine research abstracts see: heterocyclic compounds: heterocyclic compounds, 1-ring: pyrimidines: pyrimidine nucleosides: thymidine research

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Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogues. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Journal of the American Chemical Society

VOLUME: 126

Page Numbers: 15006-7

Journal Abbreviation: J. Am. Chem. Soc.

ISSN: 0002-7863

DAY: 24

MONTH: Nov

YEAR: 2004

Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogues. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7503056

Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogues. Keywords Mesh Terms:

KEYWORDS: Thymidine

MESH TERMS: chemistry

Chemical & Substance for Abstract: Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogues. Information

Substance Name: DNA

Registry Number: 9007-49-2

Grant and Affiliation Information for Structural rationalization of a large difference in RNA affinity despite a small difference in chemistry between two 2'-O-modified nucleic acid analogues.

AFFILIATION: Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: GM55237

ACRONYM: GM

MEDLINETA: J Am Chem Soc

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