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https://www.readbyqxmd.com/read/30536557/t-705-modified-ssrna-in-complex-with-lassa-virus-nucleoprotein-exhibits-nucleotide-splaying-and-increased-water-influx-into-the-rna-binding-pocket
#1
I Olaposi Omotuyi, Oyekanmi Nash, David Safronetz, A Ayodeji Ojo, H Tomisin Ogunwa, S Niyi Delakun
Lassa virus infection is clinically characterized by multi-organ failure in humans. Without an FDA-approved vaccine, ribavirin is the frontline drug for treatment but with attendant toxicities. 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) is an emerging alternative drug with proven anti-Lassa virus activity in experimental model. One of the mechanisms of action is its incorporation into nascent single strand RNA (ssRNA) which forms complex with Lassa nucleoprotein (LASV-NP). Here, using Molecular Dynamics simulation, the structural and electrostatics changes associated with LASV-NP- ssRNA complex has been studied when none, one or four of its bases has been substituted with T-705...
December 10, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/30517736/extensive-crispr-rna-modification-reveals-chemical-compatibility-and-structure-activity-relationships-for-cas9-biochemical-activity
#2
Daniel O'Reilly, Zachary J Kartje, Eman A Ageely, Elise Malek-Adamian, Maryam Habibian, Annabelle Schofield, Christopher L Barkau, Kushal J Rohilla, Lauren B DeRossett, Austin T Weigle, Masad J Damha, Keith T Gagnon
CRISPR (clustered regularly interspaced short palindromic repeat) endonucleases are at the forefront of biotechnology, synthetic biology and gene editing. Methods for controlling enzyme properties promise to improve existing applications and enable new technologies. CRISPR enzymes rely on RNA cofactors to guide catalysis. Therefore, chemical modification of the guide RNA can be used to characterize structure-activity relationships within CRISPR ribonucleoprotein (RNP) enzymes and identify compatible chemistries for controlling activity...
December 4, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/30405065/identification-of-a-2-o-methyluridine-nucleoside-hydrolase-using-the-metagenomic-libraries
#3
Agota Aučynaitė, Rasa Rutkienė, Daiva Tauraitė, Rolandas Meškys, Jaunius Urbonavičius
Ribose methylation is among the most ubiquitous modifications found in RNA. 2'- O -methyluridine is found in rRNA, snRNA, snoRNA and tRNA of Archaea , Bacteria , and Eukaryota . Moreover, 2'- O -methylribonucleosides are promising starting materials for the production of nucleic acid-based drugs. Despite the countless possibilities of practical use for the metabolic enzymes associated with methylated nucleosides, there are very few reports regarding the metabolic fate and enzymes involved in the metabolism of 2'- O -alkyl nucleosides...
November 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/30285540/therapeutic-oligonucleotides-state-of-the-art
#4
C I Edvard Smith, Rula Zain
Oligonucleotides (ONs) can interfere with biomolecules representing the entire extended central dogma. Antisense gapmer, steric block, spliceswitching ONs, and short interfering RNA drugs have been successfully developed. Moreover, antagomirs (antimicroRNAs), microRNA mimics, aptamers, DNAdecoys, DNAzymes, synthetic guide strands for CRISPR/Cas, and innate immunity-stimulating ONs are all in clinical trials. DNAtargeting, triplex-forming ONs and strand-invading ONs have made their mark on drug development research, but not yet as medicines...
October 4, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/30173504/from-fix-to-fit-into-the-autoptic-human-brains
#5
Beatrice Paradiso, Michele Simonato, Gaetano Thiene, Anna Lavezzi
Formalin-fixed, paraffinembedded (FFPE) human brain tissues are very often stored in formalin for long time. Formalin fixation reduces immunostaining, and the DNA/RNA extraction from FFPE brain tissue becomes suboptimal. At present, there are different protocols of fixation and several procedures and kits to extract DNA/RNA from paraffin embedding tissue, but a gold standard protocol remains distant. In this study, we analyzed four types of fixation systems and compared histo and immuno-staining. Based on our results, we propose a modified method of combined fixation in formalin and formic acid for the autoptic adult brain to obtain easy, fast, safe and efficient immunolabelling of long-stored FFPE tissue...
August 27, 2018: European Journal of Histochemistry: EJH
https://www.readbyqxmd.com/read/30139307/the-nonclinical-safety-profile-of-galnac-conjugated-rnai-therapeutics-in-subacute-studies
#6
Maja M Janas, Carole E Harbison, Victoria K Perry, Brenda Carito, Jessica E Sutherland, Akshay K Vaishnaw, Natalie D Keirstead, Garvin Warner
Short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) are the most clinically advanced oligonucleotide-based platforms. A number of N-acetylgalactosamine (GalNAc)-conjugated siRNAs (GalNAc-siRNAs), also referred to as RNA interference (RNAi) therapeutics, are currently in various stages of development, though none is yet approved. While the safety of ASOs has been the subject of extensive review, the nonclinical safety profiles of GalNAc-siRNAs have not been reported. With the exception of sequence differences that confer target RNA specificity, GalNAc-siRNAs are largely chemically uniform, containing limited number of phosphorothioate linkages, and 2'-O-methyl and 2'-deoxy-2'-fluoro ribose modifications...
August 23, 2018: Toxicologic Pathology
https://www.readbyqxmd.com/read/30112704/in-vivo-imaging-of-the-immune-response-upon-systemic-rna-cancer-vaccination-by-fdg-pet
#7
Stefanie Pektor, Lina Hilscher, Kerstin C Walzer, Isabelle Miederer, Nicole Bausbacher, Carmen Loquai, Mathias Schreckenberger, Ugur Sahin, Mustafa Diken, Matthias Miederer
BACKGROUND: [18 F]Fluoro-2-deoxy-2-D-glucose positron emission tomography (FDG-PET) is commonly used in the clinic for diagnosis of cancer and for follow-up of therapy outcome. Additional to the well-established value in tumor imaging, it bears potential to depict immune processes in modern immunotherapies. T cells enhance their glucose consumption upon activation and are crucial effectors for the success of such novel therapies. In this study, we analyzed the T cell immunity in spleen after antigen-specific stimulation of T cells via highly innovative RNA-based vaccines using FDG-PET/MRI...
August 15, 2018: EJNMMI Research
https://www.readbyqxmd.com/read/30107111/structure-activity-relationship-of-flavin-analogues-that-target-the-flavin-mononucleotide-riboswitch
#8
Quentin Vicens, Estefanía Mondragón, Francis E Reyes, Philip Coish, Paul Aristoff, Judd Berman, Harpreet Kaur, Kevin W Kells, Phil Wickens, Jeffery Wilson, Robert C Gadwood, Heinrich J Schostarez, Robert K Suto, Kenneth F Blount, Robert T Batey
The flavin mononucleotide (FMN) riboswitch is an emerging target for the development of novel RNA-targeting antibiotics. We previously discovered an FMN derivative, 5FDQD, that protects mice against diarrhea-causing Clostridium difficile bacteria. Here, we present the structure-based drug design strategy that led to the discovery of this fluoro-phenyl derivative with antibacterial properties. This approach involved the following stages: (1) structural analysis of all available free and bound FMN riboswitch structures; (2) design, synthesis, and purification of derivatives; (3) in vitro testing for productive binding using two chemical probing methods; (4) in vitro transcription termination assays; and (5) resolution of the crystal structures of the FMN riboswitch in complex with the most mature candidates...
September 20, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30097362/synthesis-and-properties-of-4-c-aminoalkyl-2-fluoro-modified-rna-oligomers
#9
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 15, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29937418/optimized-cholesterol-sirna-chemistry-improves-productive-loading-onto-extracellular-vesicles
#10
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...
August 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29906392/prodrugs-of-the-phosphoribosylated-forms-of-hydroxypyrazinecarboxamide-pseudobase-t-705-and-its-de-fluoro-analogue-t-1105-as-potent-influenza-virus-inhibitors
#11
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
https://www.readbyqxmd.com/read/29893074/-therapeutic-oligonucleotides-a-review
#12
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
https://www.readbyqxmd.com/read/29788895/synthesis-of-nucleosides-and-non-nucleosides-based-4-6-disubstituted-2-oxo-dihydropyridine-3-carbonitriles-as-antiviral-agents
#13
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
https://www.readbyqxmd.com/read/29766661/structure-based-design-of-a-eukaryote-selective-antiprotozoal-fluorinated-aminoglycoside
#14
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...
August 10, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29704785/2-fluoro-ribonucleic-acid-modified-dna-dual-probe-sensing-strategy-for-enzyme-amplified-electrochemical-detection-of-double-strand-dna-of-pml-rar%C3%AE-related-fusion-gene
#15
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
https://www.readbyqxmd.com/read/29601894/susceptibility-of-paramyxoviruses-and-filoviruses-to-inhibition-by-2-monofluoro-and-2-difluoro-4-azidocytidine-analogs
#16
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
https://www.readbyqxmd.com/read/29456020/advanced-sirna-designs-further-improve-in-vivo-performance-of-galnac-sirna-conjugates
#17
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
https://www.readbyqxmd.com/read/29390093/acute-hepatotoxicity-of-2-fluoro-modified-5-10-5-gapmer-phosphorothioate-oligonucleotides-in-mice-correlates-with-intracellular-protein-binding-and-the-loss-of-dbhs-proteins
#18
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
https://www.readbyqxmd.com/read/29344864/laser-capture-microdissection-in-traumatic-brain-injury-research-obtaining-hippocampal-subregions-and-pools-of-injured-neurons-for-genomic-analyses
#19
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
https://www.readbyqxmd.com/read/29338214/a-tool-for-the-import-of-natural-and-unnatural-nucleoside-triphosphates-into-bacteria
#20
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
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