- SYNTHESIS AND STRUCTURE OF HIGH POTENCY RNA THERAPEUTICS
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This invention provides expressible polynucleotides, which can express a target protein or polypeptide. Synthetic mRNA constructs for producing a protein or polypeptide can contain one or more 5′ UTRs, where a 5′ UTR may be expressed by a gene of a plant. In some embodiments, a 5′ UTR may be expressed by a gene of a member of Arabidopsis genus. The synthetic mRNA constructs can be used as pharmaceutical agents for expressing a target protein or polypeptide in vivo.
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- Identification of Flavin Mononucleotide as a Cell-Active Artificial N6-Methyladenosine RNA Demethylase
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N6-Methyladenosine (m6A) represents a common and highly dynamic modification in eukaryotic RNA that affects various cellular pathways. Natural dioxygenases such as FTO and ALKBH5 are enzymes that demethylate m6A residues in mRNA. Herein, the first identification of a small-molecule modulator that functions as an artificial m6A demethylase is reported. Flavin mononucleotide (FMN), the metabolite produced by riboflavin kinase, mediates substantial photochemical demethylation of m6A residues of RNA in live cells. This study provides a new perspective to the understanding of demethylation of m6A residues in mRNA and sheds light on the development of powerful small molecules as RNA demethylases and new probes for use in RNA biology.
- Xie, Li-Jun,Yang, Xiao-Ti,Wang, Rui-Li,Cheng, Hou-Ping,Li, Zhi-Yan,Liu, Li,Mao, Lanqun,Wang, Ming,Cheng, Liang
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supporting information
p. 5028 - 5032
(2019/03/17)
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- Oligonucleotides comprising a modified or non-natural nucleobase
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One aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one non-natural nucleobase. In certain embodiments, the non-natural nucleobase is difluorotolyl, nitroindolyl, nitropyrrolyl, or nitroimidazolyl. In a preferred embodiment, the non-natural nucleobase is difluorotolyl. In certain embodiments, only one of the two oligonucleotide strands comprising the double-stranded oligonucleotide contains a non-natural nucleobase. In certain embodiments, both of the oligonucleotide strands comprising the double-stranded oligonucleotide independently contain a non-natural nucleobase. In certain embodiments, the oligonucleotide strands comprise at least one modified sugar moiety. Another aspect of the present invention relates to a single-stranded oligonucleotide comprising at least one non-natural nucleobase. In a preferred embodiment, the non-natural nucleobase is difluorotolyl. In certain embodiments, the ribose sugar moiety that occurs naturally in nucleosides is replaced with a hexose sugar, polycyclic heteroalkyl ring, or cyclohexenyl group. In certain embodiments, at least one phosphate linkage in the oligonucleotide has been replaced with a phosphorothioate linkage.
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- Anti-HCV nucleoside derivatives
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The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.
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- Facile methods for the synthesis of 5-formylcytidine
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5′-O-Protected 5-methylcytidine 3 was oxidized with Na2S2O8 to give a mixture of the corresponding 5-(hydroxymethyl)- and 5-formylcytidine derivatives, 4 and 5. The hydroxymethyl group of 4 was further oxidized to a formyl group by treatment with ceric(IV) ammonium nitrate (CAN). Alternatively, 2′,3′,5′-O-protected 5-(hydroxymethyl)cytidine 10 was directly oxidized with CAN to give the desired 5-formylcytidine derivative 11. After removal of the protecting groups in each intermediate, 5-formylcytidine (6) was obtained in good yield.
- Abdel Rahman, Adel A.-H.,Wada, Takeshi,Saigo, Kazuhiko
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p. 1061 - 1063
(2007/10/03)
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- Recognition of RNA by tripler formation: Divergent effects of pyrimidine C-5 methylation
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In DNA triple helices, methylation at C-5 of thymine or cytosine is reported to have similar stabilizing effects for both bases. Here we show, however, that methylation of the same positions in RNA triplexes has distinctly different effects than in DNA. We have previously described the use of circular triplex-forming RNA oligonucleotides to recognize RNA sequences. Here it is shown that addition of C-5 methyl groups to uracils in these compounds very significantly increases not only affinity but also sequence selectivity in binding a purine-rich RNA target, as measured by thermal denaturation with various target RNAs. Surprisingly, however, addition of C-5 methyl groups to cytosines actually decreases affinity in binding RNA, while the same substitution in DNB is thermally stabilizing. Possible sources of this divergent behavior are discussed. A synthesis of 5-methylcytidine ribonucleoside 2'-O-silyl-3'-O-phosphoramidite is also described.
- Wang, Shaohui,Xu, Yanzheng,Kool, Eric T.
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p. 1043 - 1050
(2007/10/03)
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- Unusual Competition between Nitrogen and Carbon Methylation of Nucleosides by Methyl Radical in Various Aqueous Media
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Five nucleosides, adenosine, guanosine, cytidine, thymidine, and uridine, were allowed to react with methyl radical produced by homolysis of tert-butyl peracetate.The extent and sites of reaction exhibited a marked dependence on the pH of the aqueous medium.In the region of pH 1-4, the major products arose from C-methylation of the nucleosides.The purines were more reactive than the pyrimidines under these acidic conditions.In the pH range of 4-10, the extent of C-methylation decreased steadily with increasing pH while N-methylated products arising from methylationof the ring nitrogen and/or exocyclic amino groups predominated.In this pH range, the pyrimidine nucleosides were the more reactive.Beyond pH 10, the extent of methylation diminished in all cases as decomposition of tert-butyl peracetate became rampant.The C-methylation occurs by way of an addition mechanism while N-methylation appears to proceed via radical abstraction of a hydrogen from the N-H group followed by combination with methyl radical.The implications of these reactivity and methylation patterns in radical carcinogenesis are discussed.
- Zady, Mona F.,Wong, John L.
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p. 2373 - 2377
(2007/10/02)
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