Balkrishen Bhat

Isis Pharmaceuticals, Inc., Carlsbad, California, United States

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Publications (61)255.33 Total impact

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    ABSTRACT: The ss-siRNA activity in vivo requires a metabolically stable 5'-phosphate analog. In this report we used crystal structure of the 5'-phosphate binding pocket of Ago-2 bound with guide strand to design and synthesize ss-siRNAs containing various 5'-phosphate analogs. Our results indicate that the electronic and spatial orientation of the 5'-phosphate analog was critical for ss-siRNA activity. Chemically modified ss-siRNA targeting human apoC III mRNA demonstrated good potency for inhibiting ApoC III mRNA and protein in transgenic mice. Moreover, ApoC III ss-siRNAs were able to reduce the triglyceride and LDL cholesterol in transgenic mice demonstrating pharmacological effect of ss-siRNA. Our study provides guidance to develop surrogate phosphate analog for ss-siRNA and demonstrates that ss-siRNA provides an alternative strategy for therapeutic gene silencing. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
    Nucleic Acids Research 03/2015; DOI:10.1093/nar/gkv162 · 8.81 Impact Factor
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    ABSTRACT: Pulmonary hypertension (PH) is a complex disorder, spanning several known vascular cell types. Recently, we identified the microRNA-130/301 (miR-130/301) family as a regulator of multiple pro-proliferative pathways in PH, but the true breadth of influence of the miR-130/301 family across cell types in PH may be even more extensive. Here, we employed targeted network theory to identify additional pathogenic pathways regulated by miR-130/301, including those involving vasomotor tone. Guided by these predictions, we demonstrated, via gain- and loss-of-function experimentation in vitro and in vivo, that miR-130/301-specific control of the peroxisome proliferator-activated receptor gamma (PPARgamma) regulates a panel of vasoactive factors communicating between diseased pulmonary vascular endothelial and smooth muscle cells. Of these, the vasoconstrictive factor endothelin-1 serves as an integral point of communication between the miR-130/301-PPARgamma axis in endothelial cells and contractile function in smooth muscle cells. Thus, resulting from an in silico analysis of the architecture of the PH disease gene network coupled with molecular experimentation in vivo, these findings clarify the expanded role of the miR-130/301 family in the global regulation of PH. They further emphasize the importance of molecular crosstalk among the diverse cellular populations involved in PH. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
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    ABSTRACT: MicroRNAs (miRNAs), small RNA molecules that post-transcriptionally regulate mRNA expression, are crucial in diverse developmental and physiological programs and their misregulation can lead to disease. Chemically modified oligonucleotides have been developed to modulate miRNA activity for therapeutic intervention in disease settings, but their mechanism of action has not been fully elucidated. Here we show that the miRNA inhibitors (anti-miRs) physically associate with Argonaute proteins in the context of the cognate target miRNA in vitro and in vivo. The association is mediated by the seed region of the miRNA and is sensitive to the placement of chemical modifications. Furthermore, the targeted miRNAs are stable and continue to be associated with Argonaute. Our results suggest that anti-miRs specifically associate with Argonaute-bound miRNAs, preventing association with target mRNAs, which leads to subsequent stabilization and thus increased expression of the targeted mRNAs.
    PLoS ONE 07/2014; 9(7):e100951. DOI:10.1371/journal.pone.0100951 · 3.53 Impact Factor
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    ABSTRACT: Development of the vascular disease pulmonary hypertension (PH) involves disparate molecular pathways that span multiple cell types. MicroRNAs (miRNAs) may coordinately regulate PH progression, but the integrative functions of miRNAs in this process have been challenging to define with conventional approaches. Here, analysis of the molecular network architecture specific to PH predicted that the miR-130/301 family is a master regulator of cellular proliferation in PH via regulation of subordinate miRNA pathways with unexpected connections to one another. In validation of this model, diseased pulmonary vessels and plasma from mammalian models and human PH subjects exhibited upregulation of miR-130/301 expression. Evaluation of pulmonary arterial endothelial cells and smooth muscle cells revealed that miR-130/301 targeted PPARγ with distinct consequences. In endothelial cells, miR-130/301 modulated apelin-miR-424/503-FGF2 signaling, while in smooth muscle cells, miR-130/301 modulated STAT3-miR-204 signaling to promote PH-associated phenotypes. In murine models, induction of miR-130/301 promoted pathogenic PH-associated effects, while miR-103/301 inhibition prevented PH pathogenesis. Together, these results provide insight into the systems-level regulation of miRNA-disease gene networks in PH with broad implications for miRNA-based therapeutics in this disease. Furthermore, these findings provide critical validation for the evolving application of network theory to the discovery of the miRNA-based origins of PH and other diseases.
    Journal of Clinical Investigation 06/2014; 124(8). DOI:10.1172/JCI74773 · 13.77 Impact Factor
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    ABSTRACT: We report the structure activity relationships of short 14-mer phosphorothioate gapmer antisense oligonucleotides (ASOs) modified with α-L-locked nucleic acid (LNA) and related modifications targeting phosphatase and tensin homologue (PTEN) messenger RNA in mice. α-L-LNA represents the α-anomer of enantio-LNA and modified oligonucleotides show LNA like binding affinity for complementary RNA. In contrast to sequence matched LNA gapmer ASOs which showed elevations in plasma alanine aminotransferase (ALT) levels indicative of hepatotoxicity, gapmer ASOs modified with α-L-LNA and related analogs in the flanks showed potent downregulation of PTEN messenger RNA in liver tissue without producing elevations in plasma ALT levels. However, the α-L-LNA ASO showed a moderate dose-dependent increase in liver and spleen weights suggesting a higher propensity for immune stimulation. Interestingly, replacing α-L-LNA nucleotides in the 3'- and 5'-flanks with R-5'-Me-α-L-LNA but not R-6'-Me- or 3'-Me-α-L-LNA nucleotides, reversed the drug induced increase in organ weights. Examination of structural models of dinucleotide units suggested that the 5'-Me group increases steric bulk in close proximity to the phosphorothioate backbone or produces subtle changes in the backbone conformation which could interfere with recognition of the ASO by putative immune receptors. Our data suggests that introducing steric bulk at the 5'-position of the sugar-phosphate backbone could be a general strategy to mitigate the immunostimulatory profile of oligonucleotide drugs. In a clinical setting, proinflammatory effects manifest themselves as injection site reactions and flu-like symptoms. Thus, a mitigation of these effects could increase patient comfort and compliance when treated with ASOs.Molecular Therapy - Nucleic Acids (2012) 1, e47; doi:10.1038/mtna.2012.34; published online 18 September 2012.
    Molecular Therapy 10/2012; 1:e47. DOI:10.1038/mtna.2012.34 · 6.43 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) bind to mRNAs and fine-tune protein output by affecting mRNA stability and/or translation. miR-21 is a ubiquitous, highly abundant, and stress-responsive miRNA linked to several diseases, including cancer, fibrosis, and inflammation. Although the RNA silencing activity of miR-21 in diseased cells has been well documented, the roles of miR-21 under healthy cellular conditions are not well understood. Here, we show that pharmacological inhibition or genetic deletion of miR-21 in healthy mouse liver has little impact on regulation of canonical seed-matched mRNAs and only a limited number of genes enriched in stress response pathways. These surprisingly weak and selective regulatory effects on known and predicted target mRNAs contrast with those of other abundant liver miRNAs such as miR-122 and let-7. Moreover, miR-21 shows greatly reduced binding to polysome-associated target mRNAs compared to miR-122 and let-7. Bioinformatic analysis suggests that reduced thermodynamic stability of seed pairing and target binding may contribute to this deficiency of miR-21. Significantly, these trends are reversed in human cervical carcinoma (HeLa) cells, where miRNAs including miR-21 show enhanced target binding within polysomes and where miR-21 triggers strong degradative activity toward target mRNAs. Taken together, our results suggest that, under normal cellular conditions in liver, miR-21 activity is maintained below a threshold required for binding and silencing most of its targets. Consequently, enhanced association with polysome-associated mRNA is likely to explain in part the gain of miR-21 function often found in diseased or stressed cells.
    RNA 06/2012; 18(8):1510-26. DOI:10.1261/rna.033308.112 · 4.62 Impact Factor
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    ABSTRACT: The synthesis, biophysical, structural, and biological properties of both isomers of 3'-fluoro hexitol nucleic acid (FHNA and Ara-FHNA) modified oligonucleotides are reported. Synthesis of the FHNA and Ara-FHNA thymine phosphoramidites was efficiently accomplished starting from known sugar precursors. Optimal RNA affinities were observed with a 3'-fluorine atom and nucleobase in a trans-diaxial orientation. The Ara-FHNA analog with an equatorial fluorine was found to be destabilizing. However, the magnitude of destabilization was sequence-dependent. Thus, the loss of stability is sharply reduced when Ara-FHNA residues were inserted at pyrimidine-purine (Py-Pu) steps compared to placement within a stretch of pyrimidines (Py-Py). Crystal structures of A-type DNA duplexes modified with either monomer provide a rationalization for the opposing stability effects and point to a steric origin of the destabilization caused by the Ara-FHNA analog. The sequence dependent effect can be explained by the formation of an internucleotide C-F···H-C pseudo hydrogen bond between F3' of Ara-FHNA and C8-H of the nucleobase from the 3'-adjacent adenosine that is absent at Py-Py steps. In animal experiments, FHNA-modified antisense oligonucleotides formulated in saline showed a potent downregulation of gene expression in liver tissue without producing hepatotoxicity. Our data establish FHNA as a useful modification for antisense therapeutics and also confirm the stabilizing influence of F(Py)···H-C(Pu) pseudo hydrogen bonds in nucleic acid structures.
    Journal of the American Chemical Society 09/2011; 133(41):16642-9. DOI:10.1021/ja207086x · 11.44 Impact Factor
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    The Journal of clinical investigation 02/2011; 121(2):461-2; author reply 462-3. DOI:10.1172/JCI45938 · 13.77 Impact Factor
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    ABSTRACT: Provided herein are novel 5'-(S)-CH3 substituted bicyclic nucleosides I, wherein B is nucleobase; one of T1 and T2 is H or a hydroxy protecting group and the other of T1 and T2 is H, a hydroxy protecting group or a reactive phosphorus group; G is a diradical moiety selected from -[C(R1R2)]n-, -C(R1)=C(R2)-, -C(R1)=C(R2)-C(R3R4)-, -C[=C(R1R2)]-C(R3R4)-, -C(R1R2)-C[=C(R3R4)]-, -C(O)-N(R7)-C(R1R2)-, -C(R1R2)-N(R7)-C(R3R4)-, -C(R1R2)-N(R7)-O-, -C(R1R2)-O-N(R7)-, -C(R1R2)-N(OR3)-, -C(R1R2)-C(R3R4)-N(R7)-, -C(R1R2)-O-OC(R3R4)-, -C(R1R2)-O-C(R3R4)-O-, -C(R1R2)-C(R3R4)-O-, -C(R1R2)-C(R3R4)-C(R5R6)-O-; R1-R6 are each independently, H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; OJ1, SJ1,SOJ1, SO2J1, CN, NJ1J2, N3, C(O)J1, C(O)OJ1, C(O)NJ1J2, protecting group;each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ3, N(J3)(J4), =NJ3, SJ3, N33, CN, OC(=L)J3, OC(=L)N(J3)(J4) and C(=L)N(J3)(J4); L is O, S, NJ5; each J1-J5 is independently, H or C1-C6 alkyl; and is from 1 to 3, and oligomeric compds. prepd. therefrom and methods of using the oligomeric compds. More particularly, the furanose ring of each of the novel 5'-(S)-CH3 substituted bicyclic nucleosides includes a 2' to 4' bridging group. The 5'-(S)-CH3 substituted bicyclic nucleosides are expected to be useful for enhancing one or more properties of the oligomeric compds. they are incorporated into such as for example increasing the binding affinity. In certain embodiments, the oligomeric compds. provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA. Thus, nucleoside II was prepd. and incorporated into RNA duplexes. [on SciFinder(R)]
    Year: 01/2011
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    ABSTRACT: A high-resolution solution structure of a stable 42-nt RNA dimeric construct has been derived based on a high number of NMR observables including nuclear overhauser effects (NOEs), J-coupling constants and residual dipolar couplings (RDCs), which were all obtained with isotopically unlabeled molecules. Two 21-nt siRNA that efficiently hybridize consist of ribose units that were alternately substituted by 2'-fluoro or 2'-methoxy groups. Structure calculations utilized a set of H-F RDC values for all 21 2'-fluoro modified nucleotides under conditions of weak alignment achieved by Pf1 phages. A completely 2'-F/2'-OMe modified dimeric RNA construct adopts an antiparallel double-helical structure consisting of 19 Watson-Crick base pairs with additional 3' UU overhangs and a 5' phosphate group on the antisense strand. NMR data suggest that the stability of individual base pairs is not uniform throughout the construct. While most of the double helical segment exhibits well dispersed imino resonances, the last three base pairs either display uncharacteristic chemical shifts of imino protons or absence of imino resonances even at lower temperatures. Accessibility of imino protons to solvent exchange suggests a difference in stability of duplex ends, which might be of importance for incorporation of the guide siRNA strand into a RISC.
    Nucleic Acids Research 11/2010; 38(20):7298-307. DOI:10.1093/nar/gkq621 · 8.81 Impact Factor
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    ABSTRACT: As part of a program aimed at exploring the structure- activity relationships of 2',4'-bridged nucleic acid (BNA) containing antisense oligonucleotides (ASOs), we report the synthesis and biophysical and biological properties of R- and S-5'-Me LNA modified oligonucleotides. We show that introduction of a methyl group in the (S) configuration at the 5'-position is compatible with the high affinity recognition of complementary nucleic acids observed with LNA. In contrast, introduction of a methyl group in the (R) configuration reversed the stabilization effect of LNA. NMR studies indicated that the R-5'-Me group changes the orientation around torsion angle γ from the +sc to the ap range at the nucleoside level, and this may in part be responsible for the poor hybridization behavior exhibited by this modification. In animal experiments, S-5'-Me-LNA modified gapmer antisense olignucleotides showed slightly reduced potency relative to the sequence matched LNA ASOs while improving the therapeutic profile.
    Journal of Medicinal Chemistry 11/2010; 53(23). DOI:10.1021/jm101207e · 5.48 Impact Factor
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    ABSTRACT: A highly convergent free radical coupling of alkyl iodides and oximes, mediated by bis(trimethylstannyl) benzopinacolate (8), has been utilized to prepare a series of dimeric nucleosides as mimics of natural nucleic acids. The systematic optimization of the reaction conditions allowed for the single-step conversion of the appropriate iodides and oximes into the 2'-deoxy dimers 9 in moderate to excellent yields. For example, the reaction of 3'-deoxy-3'-iodo-5'-(triphenylmethyl)thymidine (6a) with 3'-O-(tert-butyldiphenylsilyl)-5'-O-(methyleneimino)thymidine (7a) in the presence of 8 in degassed benzene gave an 81% yield of 3'-de(oxyphosphinico)-3'-(methyleneimino)-5'-O-(triphenylmethyl)thymidylyl-(3'-->5')-3'-O-(tert-butyldiphenylsilyl)thymidine (9a). Similarly prepared were dimers containing both pyrimidine (thymine, 5-methylcytosine) and purine (adenine, guanine) bases. The reaction was highly stereoselective, giving only a single dimeric species having the ribo-configuration of the newly introduced C-3'-branched methylene moiety. Also prepared were dimers 16, incorporating 2'-O-methyl ribonucleosides in both halves of the dimer. This required the synthesis of 3'-deoxy-3'-iodo-2'-O-methyl nucleosides 12 as well as 2'-O-methyl-5'-O-methyleneimino nucleosides 15. For example, 5'-O-(tert-butyldiphenylsilyl)-3'-deoxy-3'-iodo-2'-O-methyl-5-methyluridine (12e) was prepared in 80% yield by displacement of the corresponding triflate with Bu(4)NI. Also prepared were the suitably protected 3'-deoxy-3'-iodo adenosine and guanosine derivatives. Compounds 15 were prepared in high yield by a regioselective Mitsunobu reaction to give the corresponding 5'-O-phthalimido nucleosides 13, which were subsequently converted to the requisite oximes 15. In the 2'-O-methyl series, the pinacolate coupling reaction proceeded with efficiency equal to that observed for the 2'-deoxy series 9, but with slightly less stereoselectivity, giving predominantly the C-3'ribo products 16, contaminated with 5-25% of the epimeric material. Mixed base dimers containing both pyrimidine and purine bases at all possible positions, including purine-purine dimers were prepared. The hydroxylamine or methyleneimino (MI) backbone of several representative dimers so prepared was converted via methylation to give the corresponding methylenemethylimino (MMI)-linked compounds, which are novel phosphate surrogates for use in antisense oligonucleotides.
    The Journal of Organic Chemistry 03/2010; 61(23):8186-8199. DOI:10.1002/chin.199712220 · 4.64 Impact Factor
  • B. BHAT, Y. S. SANGHVI
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 03/2010; 29(11). DOI:10.1002/chin.199811252
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 03/2010; 29(9). DOI:10.1002/chin.199809225
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    ABSTRACT: MicroRNAs (miRNAs) are increasingly implicated in the regulation of metastasis. Despite their potential as targets for anti-metastatic therapy, miRNAs have only been silenced in normal tissues of rodents and nonhuman primates. Therefore, the development of effective approaches for sequence-specific inhibition of miRNAs in tumors remains a scientific and clinical challenge. Here we show that systemic treatment of tumor-bearing mice with miR-10b antagomirs-a class of chemically modified anti-miRNA oligonucleotide-suppresses breast cancer metastasis. Both in vitro and in vivo, silencing of miR-10b with antagomirs significantly decreases miR-10b levels and increases the levels of a functionally important miR-10b target, Hoxd10. Administration of miR-10b antagomirs to mice bearing highly metastatic cells does not reduce primary mammary tumor growth but markedly suppresses formation of lung metastases in a sequence-specific manner. The miR-10b antagomir, which is well tolerated by normal animals, appears to be a promising candidate for the development of new anti-metastasis agents.
    Nature Biotechnology 03/2010; 28(4):341-7. DOI:10.1038/nbt.1618 · 39.08 Impact Factor
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    ABSTRACT: To identify chemistries and strategies to improve the potency of MOE second generation ASOs, we have evaluated gapmer antisense oligonucleotides containing BNAs having N-O bonds. These modifications include N-MeO-amino BNA, N-Me-aminooxy BNA, 2',4'-BNA(NC)[NMe], and 2',4'-BNA(NC) bridged nucleoside analogues. These modifications provided increased thermal stability and improved in vitro activity compared to the corresponding ASO containing the MOE modification. Additionally, ASOs containing N-MeO-amino BNA, N-Me-aminooxy BNA, and 2',4'-BNA(NC)[NMe] modifications showed improved in vivo activity (>5-fold) compared to MOE ASO. Importantly, toxicity parameters, such as AST, ALT, liver, kidney, and body weights, were found to be normal for N-MeO-amino BNA, N-Me-aminooxy BNA, and 2',4'-BNA(NC)[NMe] ASO treated animals. The data generated in these experiments suggest that N-MeO-amino BNA, N-Me-aminooxy BNA, and 2',4'-BNA(NC)[NMe] are useful modifications for applications in both antisense and other oligonucleotide based drug discovery efforts.
    Journal of Medicinal Chemistry 02/2010; 53(4):1636-50. DOI:10.1021/jm9013295 · 5.48 Impact Factor
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    ABSTRACT: We have recently shown that combining the structural elements of 2'O-methoxyethyl (MOE) and locked nucleic acid (LNA) nucleosides yielded a series of nucleoside modifications (cMOE, 2',4'-constrained MOE; cEt, 2',4'-constrained ethyl) that display improved potency over MOE and an improved therapeutic index relative to that of LNA antisense oligonucleotides. In this report we present details regarding the synthesis of the cMOE and cEt nucleoside phosphoramidites and the biophysical evaluation of oligonucleotides containing these nucleoside modifications. The synthesis of the cMOE and cEt nucleoside phosphoramidites was efficiently accomplished starting from inexpensive commercially available diacetone allofuranose. The synthesis features the use of a seldom used 2-naphthylmethyl protecting group that provides crystalline intermediates during the synthesis and can be cleanly deprotected under mild conditions. The synthesis was greatly facilitated by the crystallinity of a key mono-TBDPS-protected diol intermediate. In the case of the cEt nucleosides, the introduction of the methyl group in either configuration was accomplished in a stereoselective manner. Ring closure of the 2'-hydroxyl group onto a secondary mesylate leaving group with clean inversion of stereochemistry was achieved under surprisingly mild conditions. For the S-cEt modification, the synthesis of all four (thymine, 5-methylcytosine, adenine, and guanine) nucleobase-modified phosphoramidites was accomplished on a multigram scale. Biophysical evaluation of the cMOE- and cEt-containing oligonucleotides revealed that they possess hybridization and mismatch discrimination attributes similar to those of LNA but greatly improved resistance to exonuclease digestion.
    The Journal of Organic Chemistry 02/2010; 75(5):1569-81. DOI:10.1021/jo902560f · 4.64 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 31(1). DOI:10.1002/chin.200001142
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    ABSTRACT: DNA consisting of 12 to 30 linked monomers were prepd., wherein the oligomeric compd. comprises at least 4 regions, wherein each monomer within each region comprises the same type of sugar moiety and wherein the sugar moieties of the monomers of adjacent regions are different from one another; and wherein: at least one region comprises 2-20 linked monomers and each of the other regions independently comprises 1-20 linked monomers; and wherein at least one region is a tetrahydropyran region, wherein each tetrahydropyran region independently comprises one or more tetrahydropyran nucleoside analog I, wherein Bx is a heterocyclic base moiety; T3 and T4 are independently internucleoside linking group or one of T3 and T4 is H, hydroxy protecting group, a linked conjugate group or a 5' or 3'-terminal group; q1-q7 are independently, H, alkyl, alkenyl, alkynyl; R3 and R4 are independently H, hydroxy, halogen, alkyl, alkoxy. Certain such antisense compds. are useful as RNase H antisense compds., as RNAi compds., and/or as modulators of splicing. Thus, nucleoside phosphoramidite II was prepd. and used in prepn. of antisense DNA as modulators of splicing and for treating a disease by inhibiting or altering gene expression. [on SciFinder(R)]
    Year: 01/2010
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    ABSTRACT: In a search to identify chemical modifications to improve the properties of siRNA, we have investigated the effect of the 2 '-O-methyl-2-thiouridine modification on the biological activity of siRNA. Our results indicate that judicious placement of 2 '-O-methyl-2-thiouridine residues could lead to modified siRNA with activity in mammalian cells.
    Nucleosides Nucleotides &amp Nucleic Acids 10/2009; 28(10):902-10. DOI:10.1080/15257770903316145 · 0.89 Impact Factor

Publication Stats

2k Citations
255.33 Total Impact Points

Institutions

  • 2000–2015
    • Isis Pharmaceuticals, Inc.
      Carlsbad, California, United States
  • 2004–2010
    • Isis Pharmaceuticals, Inc.
      Carlsbad, California, United States
  • 2008
    • Allegheny College
      Мийдвил, Pennsylvania, United States
  • 2003
    • Merck
      • Department of Medicinal Chemistry
      Whitehouse Station, New Jersey, United States
  • 2001
    • McGill University
      • Department of Chemistry
      Montréal, Quebec, Canada