Fluoro RNA

Gut microbiota affects the gut-brain axis; hence, the modulation of the microbiota has been proposed as a potential therapeutic strategy for cerebral ischemia/reperfusion injury (CIRI). However, the role and mechanism of the gut microbiota in regulating microglial polarization during CIRI remain poorly understood. Herein, using a middle cerebral artery occlusion and reperfusion (MCAO/R) rat model, we evaluated changes in the gut microbiota after CIRI and the potential effects of fecal microbiota transplant (FMT) on the brain...

RNA aptamers provide useful biological probes and therapeutic agents. New methodologies to screen RNA aptamers will be valuable by complementing the traditional Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Meanwhile, repurposing clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated systems (Cas) has expanded their utility far beyond their native nuclease function. Here, CRISmers, a CRISPR/Cas-based novel screening system for RNA aptamers based on binding to a chosen protein of interest in a cellular context, is presented...

Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide, FPV), an active pharmaceutical component of the drug discovered and registered in March 2014 in Japan under the name Avigan, with an indication for pandemic influenza, has been studied. The study of this compound was prompted by the idea that effective processes of recognition and binding of FPV to the nucleic acid are affected predominantly by the propensity to form intra- and intermolecular interactions. Three nuclear quadrupole resonance experimental techniques, namely 1 H-14 N cross-relaxation, multiple frequency sweeps, and two-frequency irradiation, followed by solid-state computational modelling (density functional theory supplemented by the quantum theory of atoms in molecules, 3D Hirshfeld Surfaces, and reduced density gradient) approaches were applied...

BACKGROUND/AIM: Tumor suppressive microRNAs (miR) are frequently down-regulated during cancer development. The application of synthetic miR molecules restoring suppressed miR, therefore, opens up innovative possibilities in future anticancer therapy. The potential application, however, is limited by the instability of RNA molecules. The presented proof-of-principle study evaluates the potential of using synthetic chemically modified miR molecules as anticancer drugs. MATERIALS AND METHODS: Chemically synthesized miR-1 molecules containing two 2'-O-RNA modifications, 2'-O-methyl- and 2'-fluoro-derivatives, introduced at different positions of the 3'-terminus, were transfected into prostate cancer (PC) cells (LNCaP, PC-3)...

β-D-N4 -hydroxycytidine (NHC, EIDD-1931) is a nucleoside analogue that exhibits broad spectrum antiviral activity against a variety of RNA viruses. Herein, we report the synthesis of a series of lipid prodrugs of NHC and a novel 3'-fluoro modified NHC analogue, and evaluation of their antiviral activity against five variants of SARS-CoV-2. All lipid prodrugs showed potent antiviral activity against the tested SARS-CoV-2 variants with EC50 values in the range of 0.31-3.51 μM, which were comparable to those of NHC or higher than those of remdesivir and molnupiravir...

AT-752 is a guanosine analogue prodrug active against dengue virus (DENV). In infected cells, it is metabolized into 2'-methyl-2'-fluoro guanosine 5'-triphosphate (AT-9010) which inhibits RNA synthesis in acting as a RNA chain terminator. Here we show that AT-9010 has several modes of action on DENV full-length NS5. AT-9010 does not inhibit the primer pppApG synthesis step significantly. However, AT-9010 targets two NS5-associated enzyme activities, the RNA 2'-O-MTase and the RNA-dependent RNA polymerase (RdRp) at its RNA elongation step...

Eighteen nucleic acid therapeutics have been approved for treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides (ASOs), splice-switching oligonucleotides (SSOs), RNA interference (RNAi) and an RNA aptamer against a protein. Among the diseases targeted by this new class of drugs are homozygous familial hypercholesterolemia, spinal muscular atrophy, Duchenne muscular dystrophy, hereditary transthyretin-mediated amyloidosis, familial chylomicronemia syndrome, acute hepatic porphyria, and primary hyperoxaluria...

Environmental exposure to fibers of respirable size has been identified as a risk for public health. Experimental evidence has revealed that a variety of fibers, including fluoro-edenite, can develop chronic respiratory diseases and elicit carcinogenic effects in humans. Fluoro-edenite (FE) is a silicate mineral first found in Biancavilla (Sicily, Italy) in 1997. Environmental exposure to its fibers has been correlated with a cluster of malignant pleural mesotheliomas. This neoplasm represents a public health problem due to its long latency and to its aggression not alerted by specific symptoms...

This study aimed to identify a distant-recurrence image biomarker in NSCLC by investigating correlations between heterogeneity functional gene expression and fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography (18 F-FDG PET) image features of NSCLC patients. RNA-sequencing data and 18 F-FDG PET images of 53 patients with NSCLC (19 with distant recurrence and 34 without recurrence) from The Cancer Imaging Archive and The Cancer Genome Atlas Program databases were used in a combined analysis. Weighted correlation network analysis was performed to identify gene groups related to distant recurrence...

INTRODUCTION: Cases of acute myocarditis have been after administration of the BNT162b2 and Ad26.COV2.S vaccine. OBJECTIVE: Describe another possible mechanism of myocarditis after COVID-19 vaccination. CASE PRESENTATION: We describe the clinical case of a 72-year-old female with pleuritic chest pain one week after the third of the BNT162b2 mRNA vaccine. Serological tests for cardiotropic pathogens were negative, and autoimmunity screening was positive with anti-nuclear antibody (ANA) in 1:160 dilution, Anti-double-stranded DNA (anti-dsDNA), and anti-histone antibodies...

A synthesis of 2'-fluoro and 2'-methoxy N6-methyladenosine phosphoramidites and their successful incorporation into oligonucleotides is reported. 2'-fluoro and 2́-methoxy modifications of sugars in siRNAs are known to aid stability and N6-methylation modifies the potency of therapeutic silencing RNAs (siRNA). We demonstrate that a combination of those modifications incorporated into the antisense strand of siRNA leads to efficient knockdown of a target gene in cells. This work broadens the available pool of chemical modifications of therapeutic siRNAs and provides tools for their efficient synthesis...

Atherosclerosis, a condition characterized by thickening of the arteries due to lipid deposition, is the major contributor to and hallmark of cardiovascular disease. Although great progress has been made in lowering the lipid plaques in patients, the conventional therapies fail to address the needs of those that are intolerant or non-responsive to the treatment. Therefore, additional novel therapeutic approaches are warranted. We have previously shown that increasing the cellular amounts of microRNA-30c (miR-30c) with the aid of viral vectors or liposomes can successfully reduce plasma cholesterol and atherosclerosis in mice...

In nucleic acid drug discovery, it is extremely important to develop a technology to understand the distribution in target organs and to trace the degradation process in the body in order to optimize the structure and improve the efficiency of the clinical trial process. Since nucleic acid drugs are essentially metabolically degraded into numerous fragments, labeling at the internal position is preferable to that at the terminus. Due to the high molar specific activity of tritium, various approaches for tritium-labeling have been studied for nucleic acid drugs...

The antiviral pseudo-base T705 and its de-fluoro analog T1106 mimic adenine or guanine and can be competitively incorporated into nascent RNA by viral RNA-dependent RNA polymerases. Although dispersed, single pseudo-base incorporation is mutagenic, consecutive incorporation causes polymerase stalling and chain termination. Using a template encoding single and then consecutive T1106 incorporation four nucleotides later, we obtained a cryogenic electron microscopy structure of stalled influenza A/H7N9 polymerase...

Cognitive impairment caused by systemic chemotherapy is a critical question that perplexes the effective implementation of clinical treatment, but related molecular events are poorly understood. Herein, we show that bortezomib exposure leads to microglia activation and cognitive impairment, this occurs along with decreased nuclear translocation of TFEB (transcription factor EB), which is linked to macroautophagy/autophagy disorder, STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL23A (interleukin 23 subunit alpha) expression...

UNLABELLED: With few available effective interventions, emergence of novel mutants responding poorly to existing vaccines and ever swelling newer waves of infection, SARS-CoV-2 is posing difficult challenges to mankind. This mandates development of newer and effective therapeutics to prevent loss of life and contain the spread of this deadly virus. Nsp 12 or RNA-dependent RNA polymerase (RdRp) is a suitable druggable target as it plays a central role in viral replication. Catalytically important conserved amino acid residues of RdRp were delineated through a comprehensive literature search and multiple sequence alignments...

Oligonucleotide therapeutics have great potential as a next-generation approach to treating intractable diseases. Large quantities of modified DNA/RNA containing xenobiotic nucleic acids (XNAs) must be synthesized before clinical application. In this study, the ancestral RNA ligase AncT4_2 was designed by ancestral sequence reconstruction (ASR) to perform the conjugation reaction of modified RNA fragments. AncT4_2 had superior properties to native RNA ligase 2 from T4 phage (T4Rnl2), including high productivity, a >2...

The unprecedented emergence and spread of SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, underscores the need for diagnostic and therapeutic technologies that can be rapidly tailored to novel threats. Here, we show that site-specific RNA endonuclease XNAzymes - artificial catalysts composed of single-stranded synthetic xeno-nucleic acid oligonucleotides (in this case 2'-deoxy-2'-fluoro-β-D-arabino nucleic acid) - may be designed, synthesised and screened within days, enabling the discovery of a range of enzymes targeting SARS-CoV-2 ORF1ab, ORF7b, spike- and nucleocapsid-encoding RNA...

The genome editing approach using the components of the CRISPR/Cas system has found wide application in molecular biology, fundamental medicine and genetic engineering. A promising method is to increase the efficacy and specificity of CRISPR/Cas-based genome editing systems by modifying their components. Here, we designed and chemically synthesized guide RNAs (crRNA, tracrRNA and sgRNA) containing modified nucleotides (2'-O-methyl, 2'-fluoro, LNA-locked nucleic acid) or deoxyribonucleotides in certain positions...

Xenobiotic nucleic acids (XNAs) offer tremendous potential for synthetic biology, biotechnology, and molecular medicine but their ability to mimic nucleic acids still needs to be explored. Here, to study the ability of XNA oligonucleotides to mimic tRNA, we synthesized three L-Ala-tXNAs analogs. These molecules were used in a non-ribosomal peptide synthesis involving a bacterial Fem transferase. We compared the ability of this enzyme to use amino-acyl tXNAs containing 1',5'-anhydrohexitol (HNA), 2'-fluoro ribose (2'F-RNA) and 2'-fluoro arabinose...