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Fluoro RNA

Toshifumi Kano, Yui Katsuragi, Yusuke Maeda, Yoshihito Ueno
Synthesis and properties of double-stranded RNAs (dsRNAs) and small interfering RNAs (siRNAs) containing 4'-C-aminoethyl-2'-deoxy-2'-fluorouridine are described. Thermal denaturation studies showed that incorporation of 4'-C-aminoethyl-2'-fluoro analog improved the thermal stabilities of dsRNAs and siRNAs compared to the corresponding 4'-C-aminoethyl-2'-O-methyl analog. siRNA incorporating eight 4'-aminoethyl-2'-fluoro analogs in the passenger strand showed sufficient RNAi activity at 1 nM concentration, which was similar to that of the unmodified siRNA...
August 2, 2018: Bioorganic & Medicinal Chemistry
Reka Agnes Haraszti, Rachael Miller, Marie-Cecile Didiot, Annabelle Biscans, Julia F Alterman, Matthew R Hassler, Loic Roux, Dimas Echeverria, Ellen Sapp, Marian DiFiglia, Neil Aronin, Anastasia Khvorova
Extracellular vesicles are promising delivery vesicles for therapeutic RNAs. Small interfering RNA (siRNA) conjugation to cholesterol enables efficient and reproducible loading of extracellular vesicles with the therapeutic cargo. siRNAs are typically chemically modified to fit an application. However, siRNA chemical modification pattern has not been specifically optimized for extracellular vesicle-mediated delivery. Here we used cholesterol-conjugated, hydrophobically modified asymmetric siRNAs (hsiRNAs) to evaluate the effect of backbone, 5'-phosphate, and linker chemical modifications on productive hsiRNA loading onto extracellular vesicles...
June 21, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Johanna Huchting, Evelien Vanderlinden, Matthias Winkler, Hiba Nasser, Lieve Naesens, Chris Meier
We here disclose chemical synthesis of ribonucleoside 5'-monophosphate (RMP), -diphosphate (RDP), and -triphosphate (RTP) and cycloSal-, Di PPro-, and Tri PPPro nucleotide prodrugs of the antiviral pseudobase T-1105. Moreover, we include one nucleoside diphosphate prodrug of the chemically less stable T-705. We demonstrate efficient T-1105-RDP and -RTP release from the Di PPro and Tri PPPro compounds by esterase activation. Using crude enzyme extracts, we saw rapid phosphorylation of T-1105-RDP into T-1105-RTP...
July 3, 2018: Journal of Medicinal Chemistry
Xiaolong Wang, Jingnü Xian, Gang Chen, Haibo Peng
Oligonucleotides are widely used as effective tools to regulate gene expression and drugs for targeted gene therapy. Therefore, they are potentially useful for the treatment of viral, tumor and hereditary diseases. Therapeutic oligonucleotides include antisense oligonucleotide, small interference RNA (siRNA), Ribozyme, DNAzyme, anti-gene, CpG, decoy and aptamer. Therapeutic oligonucleotides usually carry certain modifications, such as phosphorothioates, fluoro or locked nucleic acids, to enhance the stability and specificity, and reduce the side-effects, because natural oligonucleotides have poor stability in vivo, low specificity and side effects...
May 25, 2018: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
Tarek S Ibrahim, Hassan A El-Sayed, Maan T Khayat, Amany M M Al-Mahmoudy, Ahmed H Moustafa, Ayat K Saad El-Deen, Sherif A F Rostom, Siva S Panda
BACKGROUND: Viral diseases are considered main threats that face the humanity worldwide. The emergence of new viruses like influenza viruses emphasizes the significance of designing novel antiviral drugs. METHOD: The aim of this work is to synthesize a new set of nucleoside and non-nucleoside cyanopyridine, characterized and evaluated for their in vitro antiviral properties against various strains. CONCLUSION: More than compounds showed variable antiviral potential against a panel of eighteen DNA and RNA viruses...
May 22, 2018: Medicinal Chemistry
Hiroki Kanazawa, Oscar M Saavedra, Juan Pablo Maianti, Simon A Young, Luis Izquierdo, Terry K Smith, Stephen Hanessian, Jiro Kondo
Aminoglycosides (AG) are antibiotics that lower the accuracy of protein synthesis by targeting a highly conserved RNA helix of the ribosomal A-site. The discovery of AGs that selectively target the eukaryotic ribosome, but lack activity in prokaryotes, are promising as antiprotozoals for the treatment of neglected tropical diseases, and as therapies to read-through point-mutation genetic diseases. However, a single nucleobase change A1408G in the eukaryotic A-site leads to negligible affinity for most AGs. Herein we report the synthesis of 6'-fluorosisomicin, the first 6'-fluorinated aminoglycoside, which specifically interacts with the protozoal cytoplasmic rRNA A-site, but not the bacterial A-site, as evidenced by X-ray co-crystal structures...
May 15, 2018: ChemMedChem
Yun Lei, Kun Wang, Shan-Yue Wu, Dan-Dan Huang, Ming Dai, Yan-Jie Zheng, Zhou-Liang Sun, Yuan-Zhong Chen, Xin-Hua Lin, Ai-Lin Liu
In the study, a novel sensing strategy based on dual-probe mode, which involved two groups of 2'-fluoro ribonucleic acid (2'-F RNA) modified probes, was designed for the detection of synthetic target double-strand DNA (dsDNA) of PML/RARα fusion genes in APL. And each pair of probes contained a thiolated capture probe (C1 or C2) immobilized on one of electrode surfaces in the dual-channel electrochemical biosensor and a biotinylated reporter probe (R1 or R2). The two groups of 2'-F RNA modified probes were separately complementary with the corresponding strand (Sa or Sb) from target dsDNA in order to prevent renaturation of target dsDNA...
July 30, 2018: Biosensors & Bioelectronics
Michael K Lo, Paul C Jordan, Sarah Stevens, Yuen Tam, Jerome Deval, Stuart T Nichol, Christina F Spiropoulou
Ebolaviruses, marburgviruses, and henipaviruses are zoonotic pathogens belonging to the Filoviridae and Paramyxoviridae families. They exemplify viruses that continue to spill over into the human population, causing outbreaks characterized by high mortality and significant clinical sequelae in survivors of infection. There are currently no approved small molecule therapeutics for use in humans against these viruses. In this study, we evaluated the antiviral activity of the nucleoside analog 4'-azidocytidine (4'N3 -C, R1479) and its 2'-monofluoro- and 2'-difluoro-modified analogs (2'F-4'N3 -C and 2'diF-4'N3 -C) against representative paramyxoviruses (Nipah virus, Hendra virus, measles virus, and human parainfluenza virus 3) and filoviruses (Ebola virus, Sudan virus, and Ravn virus)...
May 2018: Antiviral Research
Donald J Foster, Christopher R Brown, Sarfraz Shaikh, Casey Trapp, Mark K Schlegel, Kun Qian, Alfica Sehgal, Kallanthottathil G Rajeev, Vasant Jadhav, Muthiah Manoharan, Satya Kuchimanchi, Martin A Maier, Stuart Milstein
Significant progress has been made in the advancement of RNAi therapeutics by combining a synthetic triantennary N-acetylgalactosamine ligand targeting the asialoglycoprotein receptor with chemically modified small interfering RNA (siRNA) designs, including the recently described Enhanced Stabilization Chemistry. This strategy has demonstrated robust RNAi-mediated gene silencing in liver after subcutaneous administration across species, including human. Here we demonstrate that substantial efficacy improvements can be achieved through further refinement of siRNA chemistry, optimizing the positioning of 2'-deoxy-2'-fluoro and 2'-O-methyl ribosugar modifications across both strands of the double-stranded siRNA duplex to enhance stability without compromising intrinsic RNAi activity...
March 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Wen Shen, Cheryl L De Hoyos, Hong Sun, Timothy A Vickers, Xue-Hai Liang, Stanley T Crooke
We reported previously that a 2' fluoro-modified (2' F) phosphorothioate (PS) antisense oligonucleotides (ASOs) with 5-10-5 gapmer configuration interacted with proteins from Drosophila behavior/human splicing (DBHS) family with higher affinity than PS-ASOs modified with 2'-O-(2-methoxyethyl) (2' MOE) or 2',4'-constrained 2'-O-ethyl (cEt) did. Rapid degradation of these proteins and cytotoxicity were observed in cells treated with 2' F PS-ASO. Here, we report that 2' F gapmer PS-ASOs of different sequences caused reduction in levels of DBHS proteins and hepatotoxicity in mice...
March 16, 2018: Nucleic Acids Research
Deborah R Boone, Harris A Weisz, Stacy L Sell, Helen L Hellmich
The methods presented here are based on our laboratory's 15 years of experience using laser capture microdissection to obtain samples for the study of gene expression after traumatic brain injury (TBI) using a well-established rat model of experimental TBI. Here, we describe how to use the ArcturusXT laser capture microdissection system to capture swaths of specific regions of the rat hippocampus as well as specific neuronal populations defined by Fluoro-Jade C staining. Staining with Fluoro-Jade C identifies a neuron that is in the process of degeneration...
2018: Methods in Molecular Biology
Aaron W Feldman, Emil C Fischer, Michael P Ledbetter, Jen-Yu Liao, John C Chaput, Floyd E Romesberg
Nucleoside triphosphates play a central role in biology, but efforts to study these roles have proven difficult because the levels of triphosphates are tightly regulated in a cell and because individual triphosphates can be difficult to label or modify. In addition, many synthetic biology efforts are focused on the development of unnatural nucleoside triphosphates that perform specific functions in the cellular environment. In general, both of these efforts would be facilitated by a general means to directly introduce desired triphosphates into cells...
January 31, 2018: Journal of the American Chemical Society
Amer F Saleh, Martin Bachman, Catherine C Priestley, Nigel J Gooderham, Patrik Andersson, Scott P Henry, Nicholas J Edmunds, Mick D Fellows
Nucleoside analogs with 2'-modified sugar moieties are often used to improve the RNA target affinity and nuclease resistance of therapeutic oligonucleotides in preclinical and clinical development. Despite their enhanced nuclease resistance, oligonucleotides could slowly degrade releasing nucleoside analogs that have the potential to become phosphorylated and incorporated into cellular DNA and RNA. For the first time, the phosphorylation and DNA/RNA incorporation of 2'-O-(2-methoxyethyl) (2'-O-MOE) nucleoside analogs have been investigated...
May 1, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
Ulrich Hahn
Interleukin-6 (IL-6) is a key player in inflammation and the main factor for the induction of acute phase protein biosynthesis. Further to its central role in many aspects of the immune system, IL-6 regulates a variety of homeostatic processes. To interfere with IL-6 dependent diseases, such as various autoimmune diseases or certain cancers like multiple myeloma or hepatocellular carcinoma associated with chronic inflammation, it might be a sensible strategy to target human IL-6 receptor (hIL-6R) presenting cells with aptamers...
December 6, 2017: International Journal of Molecular Sciences
Michiko Kimoto, Adam J Meyer, Ichiro Hirao, Andrew D Ellington
Thermostable T7 RNA polymerase variants were explored for genetic alphabet expansion transcription involving the unnatural Ds-Pa pair. One variant exhibited high incorporation efficiencies of functionally modified Pa substrates and enabled the simultaneous incorporation of 2'-fluoro-nucleoside triphosphates of pyrimidines into transcripts, allowing the generation of novel, highly functional RNA molecules.
November 14, 2017: Chemical Communications: Chem Comm
Kevin R Fales, F George Njoroge, Harold B Brooks, Stefan Thibodeaux, Alicia Torrado, Chong Si, James L Toth, Jefferson R Mc Cowan, Kenneth D Roth, Kenneth Jeff Thrasher, Kwame Frimpong, Matthew R Lee, Robert D Dally, Timothy A Shepherd, Timothy Barrett Durham, Brandon J Margolis, Zhipei Wu, Yong Wang, Shane Atwell, Jing Wang, Yu-Hua Hui, Timothy I Meier, Susan A Konicek, Sandaruwan Geeganage
A hallmark of cancer is unbridled proliferation that can result in increased demand for de novo synthesis of purine and pyrimidine bases required for DNA and RNA biosynthesis. These synthetic pathways are frequently upregulated in cancer and involve various folate-dependent enzymes. Anti-folates have a proven record as clinically used oncolytic agents. Our recent research efforts have produced LSN 3213128 (compound 28a), a novel, selective, non-classical, orally-bioavailable anti-folate with potent and specific inhibitory activity for aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT), an enzyme in the purine biosynthetic pathway...
October 26, 2017: Journal of Medicinal Chemistry
Jae In Jung, Seung Ryul Han, Seong-Wook Lee
OBJECTIVES: To develop an RNA aptamer specific for the methyltransferase (MTase) of dengue virus (DENV) which is essential for viral genome replication and translation acting directly on N-7 and 2'-O-methylation of the type-I cap structure of the viral RNA. RESULTS: We identified 2'-fluoro-modified RNA aptamers that can specifically bind DENV serotype 2 (DENV2) MTase using systematic evolution of ligands by exponential enrichment technology. We truncated the chosen aptamer into a 45-mer RNA sequence that can bind DENV2 MTase with K d  ~ 28 nM and inhibit N-7 methylation activity of the protein...
February 2018: Biotechnology Letters
William Copp, Alexey Y Denisov, Jingwei Xie, Anne M Noronha, Christopher Liczner, Nozhat Safaee, Christopher J Wilds, Kalle Gehring
Polyadenylate (poly(A)) has the ability to form a parallel duplex with Hoogsteen adenine:adenine base pairs at low pH or in the presence of ammonium ions. In order to evaluate the potential of this structural motif for nucleic acid-based nanodevices, we characterized the effects on duplex stability of substitutions of the ribose sugar with 2'-deoxyribose, 2'-O-methyl-ribose, 2'-deoxy-2'-fluoro-ribose, arabinose and 2'-deoxy-2'-fluoro-arabinose. Deoxyribose substitutions destabilized the poly(A) duplex both at low pH and in the presence of ammonium ions: no duplex formation could be detected with poly(A) DNA oligomers...
September 29, 2017: Nucleic Acids Research
Christina Kratschmer, Matthew Levy
There is increasing interest in the use of aptamers for the development of therapeutics. However, as oligonucleotides, aptamers are susceptible to nuclease degradation; poor serum stability is likely to negatively affect in vivo function. Modified nucleotides have been used to thwart nuclease degradation. However, few studies report the serum stability of selected aptamers. In this study, we examined the effect of various chemical modifications (2'-deoxy, 2'-hydroxyl, 2'-fluoro, and 2'-O-methyl) on the stability of a control oligonucleotide sequence following incubation in frozen human, fresh mouse, and fresh human serum...
December 2017: Nucleic Acid Therapeutics
Elise Malek-Adamian, Dale C Guenther, Shigeo Matsuda, Saúl Martínez-Montero, Ivan Zlatev, Joel Harp, Mihai Burai Patrascu, Donald J Foster, Johans Fakhoury, Lydia Perkins, Nicolas Moitessier, Rajar M Manoharan, Nate Taneja, Anna Bisbe, Klaus Charisse, Martin Maier, Kallanthottathil G Rajeev, Martin Egli, Muthiah Manoharan, Masad J Damha
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. 1 H 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...
October 18, 2017: Journal of the American Chemical Society
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