Diversity-oriented solid-phase synthesis and biological evaluation of oligonucleotide hairpins as HIV-1 RT RNase H inhibitors

Hannoush, Rami N.; Min, Kyoungdoug; Damha, Masad J.

doi:10.1093/nar/gkh948

Cited by 10 publications

(8 citation statements)

References 43 publications

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“…Shorter chain oligonucleotides (less than 8-mers) with lesser number of charges and smaller molecular weight compared to 20-mer oligonucleotides represent a promising class of novel molecules with potential therapeutic and diagnostic properties. 6 Indeed, recent reports [7][8][9][10] suggest that mono-, di-, tri-, and short chain oligonucleotides possess significant biological activity that can be exploited for therapeutic applications. In this context, we have recently reported that certain di-, and tri-nucleoside phosphorothioate (PS) and phosphoramidate analogs exhibit potent anti-HBV activity in vitro and in vivo.…”

mentioning

confidence: 99%

Anti-HBV nucleotide prodrug analogs: Synthesis, bioreversibility, and cytotoxicity studies

Padmanabhan

Coughlin

Zhang

et al. 2006

Bioorganic & Medicinal Chemistry Letters

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mentioning

confidence: 99%

Anti-HBV nucleotide prodrug analogs: Synthesis, bioreversibility, and cytotoxicity studies

Padmanabhan

Coughlin

Zhang

et al. 2006

Bioorganic & Medicinal Chemistry Letters

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“…It has been demonstrated that 2′,5′-linked RNA are significantly more resistant toward nuclease degradation in comparison with their 3′,5′-linked analogs. Recent study showed that the 2′,5′-linked RNA loop structure is recognized by HIV-1 reverse transcriptase and acts as a potent inhibitor of RNase H activity of HIV-1 RT when present within the appropriate hairpin stem (44). New structural data contribute to the repertoire of novel RNA structural motifs that assists in the design of new 2′,5′-linked RNA aptamers and ribozymes.…”

Section: Resultsmentioning

confidence: 99%

Solution structure of a modified 2',5'-linked RNA hairpin involved in an equilibrium with duplex

Plevnik

Gdaniec²,

Plavec³

2005

Nucleic Acids Research

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The isomerization of phosphodiester functionality of nucleic acids from 3′,5′- to a less common 2′,5′-linkage influences the complex interplay of stereoelectronic effects that drive pseudorotational equilibrium of sugar rings and thus affect the conformational propensities for compact or more extended structures. The present study highlights the subtle balance of non-covalent forces at play in structural equilibrium of 2′,5′-linked RNA analogue, 3′-O-(2-methoxyethyl) substituted dodecamer *CG*CGAA*U*U*CG*CG, 3′-MOE-2′,5′-RNA, where all cytosines and uracils are methylated at C5. The NMR and UV spectroscopic studies have shown that 3′-MOE-2′,5′-RNA adopts both hairpin and duplex secondary structures, which are involved in a dynamic exchange that is slow on the NMR timescale and exhibits strand and salt concentration as well as pH dependence. Unusual effect of pH over a narrow physiological range is observed for imino proton resonances with exchange broadening observed at lower pH and relatively sharp lines observed at higher pH. The solution structure of 3′-MOE-2′,5′-RNA hairpin displays a unique and well-defined loop, which is stabilized by Watson–Crick A5·*U8 base pair and by n → π* stacking interactions of O4′ lone-pair electrons of A6 and *U8 with aromatic rings of A5 and *U7, respectively. In contrast, the stem region of 3′-MOE-2′,5′-RNA hairpin is more flexible. Our data highlight the important feature of backbone modifications that can have pronounced effects on interstrand association of nucleic acids.

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“…This destabilization was minimized when the 2′,5′- H and 3′,5′- H were incorporated into 2′,5′-RNA and RNA strands, respectively (Δ T m < −1.0°C). It is expected that longer oligomers containing this modification, particularly if they contain 2′,5′-linkages, will show adequate thermal stability, significant nuclease stability ( 23 ) and binding to mRNA targets.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and hybridization studies of oligonucleotides containing 1-(2-deoxy-2- -C-hydroxymethyl- -D-ribofuranosyl)thymine (2'- -hm-dT)

Peng¹

2005

Nucleic Acids Research

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We report the first investigation of oligoribonucleotides containing a few 1-(2-deoxy-2-α-C-hydroxymethyl-β-d-ribofuranosyl)thymine units (or 2′-hm-dT, abbreviated in this work as ‘H’). Both the 2′-CH2O-phosphoramidite and 3′-O-phosphoramidite derivatives of H were synthesized and incorporated into both 2′,5′-RNA and RNA chains. The hybridization properties of the modified oligonucleotides have been studied via thermal denaturation and circular dichroism studies. While 3′,5′-linked H was shown previously to significantly destabilize DNA:RNA hybrids and DNA:DNA duplexes (modification in the DNA strand; ΔTm ∼ −3°C/insert), we find that 2′,5′-linked H have a smaller effect on 2′,5′-RNA:RNA and RNA:RNA duplexes (ΔTm = −0.3°C and −1.2°C, respectively). The incorporation of 3′,5′-linked H into 2′,5′-RNA:RNA and RNA:RNA duplexes was found to be more destabilizing (−0.7°C and −3.6°C, respectively). Significantly, however, the 2′,5′-linked H units confer marked stability to RNA hairpins when they are incorporated into a 2′,5′-linked tetraloop structure (ΔTm = +1.5°C/insert). These results are rationalized in terms of the compact and extended conformations of nucleotides.

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Diversity-oriented solid-phase synthesis and biological evaluation of oligonucleotide hairpins as HIV-1 RT RNase H inhibitors

Cited by 10 publications

References 43 publications

Anti-HBV nucleotide prodrug analogs: Synthesis, bioreversibility, and cytotoxicity studies

Anti-HBV nucleotide prodrug analogs: Synthesis, bioreversibility, and cytotoxicity studies

Solution structure of a modified 2',5'-linked RNA hairpin involved in an equilibrium with duplex

Synthesis and hybridization studies of oligonucleotides containing 1-(2-deoxy-2- -C-hydroxymethyl- -D-ribofuranosyl)thymine (2'- -hm-dT)

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