- 4′-C-Methoxy-2′-deoxy-2′-fluoro Modified Ribonucleotides Improve Metabolic Stability and Elicit Efficient RNAi-Mediated Gene Silencing
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We designed novel 4′-modified 2′-deoxy-2′-fluorouridine (2′-F U) analogues with the aim to improve nuclease resistance and potency of therapeutic siRNAs by introducing 4′-C-methoxy (4′-OMe) as the alpha (C4′α) or beta (C4′β) epimers. The C4′α epimer was synthesized by a stereoselective route in six steps; however, both α and β epimers could be obtained by a nonstereoselective approach starting from 2′-F U. 1H NMR analysis and computational investigation of the α-epimer revealed that the 4′-OMe imparts a conformational bias toward the North-East sugar pucker, due to intramolecular hydrogen bonding and hyperconjugation effects. The α-epimer generally conceded similar thermal stability as unmodified nucleotides, whereas the β-epimer led to significant destabilization. Both 4′-OMe epimers conferred increased nuclease resistance, which can be explained by the close proximity between 4′-OMe substituent and the vicinal 5′- and 3′-phosphate group, as seen in the X-ray crystal structure of modified RNA. siRNAs containing several C4′α-epimer monomers in the sense or antisense strands triggered RNAi-mediated gene silencing with efficiencies comparable to that of 2′-F U.
- Malek-Adamian, Elise,Guenther, Dale C.,Matsuda, Shigeo,Martínez-Montero, Saúl,Zlatev, Ivan,Harp, Joel,Burai Patrascu, Mihai,Foster, Donald J.,Fakhoury, Johans,Perkins, Lydia,Moitessier, Nicolas,Manoharan, Rajar M.,Taneja, Nate,Bisbe, Anna,Charisse, Klaus,Maier, Martin,Rajeev, Kallanthottathil G.,Egli, Martin,Manoharan, Muthiah,Damha, Masad J.
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- Discovery of 4′-chloromethyl-2′-deoxy-3′,5′-di- O -isobutyryl-2′-fluorocytidine (ALS-8176), A first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection
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Respiratory syncytial virus (RSV) is a leading pathogen of childhood and is associated with significant morbidity and mortality. To date, ribavirin is the only approved small molecule drug, which has limited use. The only other RSV drug is palivizumab, a monoclonal antibody, which is used for RSV prophylaxis. Clearly, there is an urgent need for small molecule RSV drugs. This article reports the design, synthesis, anti-RSV activity, metabolism, and pharmacokinetics of a series of 4′-substituted cytidine nucleosides. Among tested compounds 4′-chloromethyl-2′-deoxy-2′-fluorocytidine (2c) exhibited the most promising activity in the RSV replicon assay with an EC50 of 0.15 μM. The 5′-triphosphate of 2c (2c-TP) inhibited RSV polymerase with an IC50 of 0.02 μM without appreciable inhibition of human DNA and RNA polymerases at 100 μM. ALS-8176 (71), the 3′,5′-di-O-isobutyryl prodrug of 2c, demonstrated good oral bioavailability and a high level of 2c-TP in vivo. Compound 71 is a first-in-class nucleoside RSV polymerase inhibitor that demonstrated excellent anti-RSV efficacy and safety in a phase 2 clinical RSV challenge study.
- Wang, Guangyi,Deval, Jerome,Hong, Jin,Dyatkina, Natalia,Prhavc, Marija,Taylor, Joshua,Fung, Amy,Jin, Zhinan,Stevens, Sarah K.,Serebryany, Vladimir,Liu, Jyanwei,Zhang, Qingling,Tam, Yuen,Chanda, Sushmita M.,Smith, David B.,Symons, Julian A.,Blatt, Lawrence M.,Beigelman, Leo
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p. 1862 - 1878
(2015/04/22)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a norovirus, with a nucleoside, a nucleotide and an analog thereof.
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Paragraph 0282
(2015/01/16)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a paramyxovirus and/or an orthomyxovirus, with a nucleoside, a nucleotide and an analog thereof.
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Paragraph 0389; 0390
(2013/07/05)
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