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Antiviral Research Feb 2022Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus 2...
Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid global emergence of SARS-CoV-2 highlights the importance and urgency for potential drugs to control the pandemic. The functional importance of RNA-dependent RNA polymerase (RdRp) in the viral life cycle, combined with structural conservation and absence of closely related homologs in humans, makes it an attractive target for designing antiviral drugs. Nucleos(t)ide analogs (NAs) are still the most promising broad-spectrum class of viral RdRp inhibitors. In this study, using our previously developed cell-based SARS-CoV-2 RdRp report system, we screened 134 compounds in the Selleckchemicals NAs library. Four candidate compounds, Fludarabine Phosphate, Fludarabine, 6-Thio-20-Deoxyguanosine (6-Thio-dG), and 5-Iodotubercidin, exhibit remarkable potency in inhibiting SARS-CoV-2 RdRp. Among these four compounds, 5-Iodotubercidin exhibited the strongest inhibition upon SARS-CoV-2 RdRp, and was resistant to viral exoribonuclease activity, thus presenting the best antiviral activity against coronavirus from a different genus. Further study showed that the RdRp inhibitory activity of 5-Iodotubercidin is closely related to its capacity to inhibit adenosine kinase (ADK).
Topics: Antiviral Agents; Cell Line; Deoxyguanosine; Drug Evaluation, Preclinical; HEK293 Cells; Humans; Microbial Sensitivity Tests; Nucleic Acid Synthesis Inhibitors; RNA, Viral; RNA-Dependent RNA Polymerase; SARS-CoV-2; Thionucleosides; Tubercidin; Vidarabine; Vidarabine Phosphate; COVID-19 Drug Treatment
PubMed: 35101534
DOI: 10.1016/j.antiviral.2022.105254 -
International Journal of Molecular... Dec 2022Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a...
Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a series of 6,9-disubstituted and 2,6,9-trisubstituted purine ribonucleosides via consecutive nucleophilic aromatic substitution, glycosylation, and deprotection of the ribofuranose unit. We prepared eight new purine nucleosides bearing unique adamantylated aromatic amines at position 6. Additionally, the ability of the synthesized purine nucleosides to form stable host-guest complexes with β-cyclodextrin (β-CD) was confirmed using nuclear magnetic resonance (NMR) and mass spectrometry (ESI-MS) experiments. The in vitro antiproliferative activity of purine nucleosides and their equimolar mixtures with β-CD was tested against two types of human tumor cell line. Six adamantane-based purine nucleosides showed an antiproliferative activity in the micromolar range. Moreover, their effect was only slightly suppressed by the presence of β-CD, which was probably due to the competitive binding of the corresponding purine nucleoside inside the β-CD cavity.
Topics: Humans; Adamantane; Purine Nucleosides; beta-Cyclodextrins; Cell Line, Tumor; Nucleosides
PubMed: 36499470
DOI: 10.3390/ijms232315143 -
Cell Death & Disease Oct 2021Proper follicle development is very important for the production of mature oocytes, which is essential for the maintenance of female fertility. This complex biological...
Proper follicle development is very important for the production of mature oocytes, which is essential for the maintenance of female fertility. This complex biological process requires precise gene regulation. The most abundant modification of mRNA, N-methyladenosine (mA), is involved in many RNA metabolism processes, including RNA splicing, translation, stability, and degradation. Here, we report that mA plays essential roles during oocyte and follicle development. Oocyte-specific inactivation of the key mA methyltransferase Mettl3 with Gdf9-Cre caused DNA damage accumulation in oocytes, defective follicle development, and abnormal ovulation. Mechanistically, combined RNA-seq and mA methylated RNA immunoprecipitation sequencing (MeRIP-seq) data from oocytes revealed, that we found METTL3 targets Itsn2 for mA modification and then enhances its stability to influence the oocytes meiosis. Taken together, our findings highlight the crucial roles of mRNA mA modification in follicle development and coordination of RNA stabilization during oocyte growth.
Topics: Adenosine; Animals; Female; Methyltransferases; Mice; Oocytes; Ovarian Follicle
PubMed: 34689175
DOI: 10.1038/s41419-021-04272-9 -
Microbial Physiology 20215-Deoxyadenosine (5dAdo) is a by-product of many radical SAM enzyme reactions in all domains of life, and an inhibitor of the radical SAM enzymes themselves. Hence,... (Review)
Review
5-Deoxyadenosine (5dAdo) is a by-product of many radical SAM enzyme reactions in all domains of life, and an inhibitor of the radical SAM enzymes themselves. Hence, pathways to recycle or dispose of this toxic by-product must exist but remain largely unexplored. In this review, we discuss the current knowledge about canonical and atypical 5dAdo salvage pathways that have been characterized in the last years. We highlight studies that report on how, in certain organisms, the salvage of 5dAdo via specific pathways can confer a growth advantage by providing either intermediates for the synthesis of secondary metabolites or a carbon source for the synthesis of metabolites of the central carbon metabolism. Yet, an alternative recycling route exists in organisms that use 5dAdo as a substrate to synthesize and excrete 7-deoxysedoheptulose, an allelopathic inhibitor of one enzyme of the shikimate pathway, thereby competing for their own niche. Remarkably, most steps of 5dAdo salvage are the result of the activity of promiscuous enzymes. This strategy enables even organisms with a small genome to synthesize bioactive compounds which they can deploy under certain conditions to gain a competitive growth advantage. We conclude emphasizing that, unexpectedly, 5dAdo salvage pathways seem not to be ubiquitously present, raising questions about the fate of such a toxic by-product in those species. This observation also suggests that additional 5dAdo salvage pathways, possibly relying on the activity of promiscuous enzymes, may exist. The future challenge will be to bring to light these "cryptic" 5dAdo recycling pathways.
Topics: Deoxyadenosines
PubMed: 34126623
DOI: 10.1159/000516105 -
Accounts of Chemical Research Sep 2023The term RNA editing refers to any structural change in an RNA molecule ( insertion, deletion, or base modification) that changes its coding properties and is not a...
The term RNA editing refers to any structural change in an RNA molecule ( insertion, deletion, or base modification) that changes its coding properties and is not a result of splicing. An important class of enzymes involved in RNA editing is the ADAR family (adenosine deaminases acting on RNA), which facilitate the deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA). Inosines are decoded as guanosines (G) in most cellular processes; hence, A-to-I editing can be considered an A-to-G substitution. Among the RNA editing enzymes, ADARs are of particular interest because a large portion of RNA editing events are due to A-to-I editing by the two catalytically active human ADARs (ADAR1 and ADAR2). ADARs have diverse roles in RNA processing, gene expression regulation, and innate immunity; and mutations in the ADAR genes and dysregulated ADAR activity have been associated with cancer, autoimmune diseases, and neurological disorders. A-to-I editing is also currently being explored for correcting disease-causing mutations in the RNA, where therapeutic guide oligonucleotides complementary to the target transcript are used to form a dsRNA substrate and site-specifically direct ADAR editing. Knowledge of the mechanism of ADAR-catalyzed reaction and the origin of its substrate selectivity will allow understanding of ADAR’s role in disease biology and expedite the process of developing ADAR-targeted therapeutics. Chemically modified oligonucleotides provide a versatile platform for modulating the activity and interrogating the structure, function, and selectivity of nucleic acid binding or modifying proteins. In this account, we provide an overview of oligonucleotide modifications that have allowed us to gain deeper understanding of ADAR’s molecular mechanisms, which we utilize in the rational design and optimization of ADAR activity modulators. First, we describe the use of the nucleoside analog 8-azanebularine (8-azaN) to generate high-affinity ADAR-RNA complexes for biochemical and biophysical studies with ADARs, with particular emphasis on X-ray crystallography. We then discuss key observations derived from the crystal structures of ADAR bound to 8-azaN-modified RNA duplexes and describe how these findings provided insight into ADAR editing optimization by introducing nucleoside modifications at various positions in synthetic guide strands. We also present the informed design of 8-azaN-modified RNA duplexes that selectively bind and inhibit ADAR1 but not the closely-related ADAR2 enzyme. Finally, we conclude with some open questions on ADAR structure and substrate recognition and share our current endeavors in the development of ADAR guide oligonucleotides and inhibitors.
Topics: Humans; RNA; Adenosine Deaminase; Hydrolases; Adenosine; Autoimmune Diseases
PubMed: 37665999
DOI: 10.1021/acs.accounts.3c00390 -
Molecular Cancer Jun 2020Since the breakthrough discoveries of DNA and histone modifications, the field of RNA modifications has gained increasing interest in the scientific community. The... (Review)
Review
Since the breakthrough discoveries of DNA and histone modifications, the field of RNA modifications has gained increasing interest in the scientific community. The discovery of N6-methyladenosine (m6A), a predominantly internal epigenetic modification in eukaryotes mRNA, heralded the creation of the field of epi-transcriptomics. This post-transcriptional RNA modification is dynamic and reversible, and is regulated by methylases, demethylases and proteins that preferentially recognize m6A modifications. Altered m6A levels affect RNA processing, degradation and translation, thereby disrupting gene expression and key cellular processes, ultimately resulting in tumor initiation and progression. Furthermore, inhibitors and regulators of m6A-related factors have been explored as therapeutic approaches for treating cancer. In the present review, the mechanisms of m6A RNA modification, the clinicopathological relevance of m6A alterations, the type and frequency of alterations and the multiple functions it regulates in different types of cancer are discussed.
Topics: Adenosine; Biomarkers, Tumor; DNA Methylation; Disease Progression; Epigenesis, Genetic; Humans; Methyltransferases; Neoplasms
PubMed: 32513173
DOI: 10.1186/s12943-020-01216-3 -
Nutrients Dec 2023, also known as "zombie fungus", is a non-poisonous mushroom that parasitizes insects for growth and development by manipulating the host system in a way that makes the... (Review)
Review
, also known as "zombie fungus", is a non-poisonous mushroom that parasitizes insects for growth and development by manipulating the host system in a way that makes the victim behave like a "zombie". These species produce promising bioactive metabolites, like adenosine, β-glucans, cordycepin, and ergosterol. has been used in traditional medicine due to its immense health benefits, as it boosts stamina, appetite, immunity, longevity, libido, memory, and sleep. Neuronal loss is the typical feature of neurodegenerative diseases (NDs) (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS)) and neurotrauma. Both these conditions share common pathophysiological features, like oxidative stress, neuroinflammation, and glutamatergic excitotoxicity. bioactives (adenosine, N-(2-hydroxyethyl)-adenosine, ergosta-7, 9 (11), 22-trien-3β-ol, active peptides, and polysaccharides) exert potential antioxidant, anti-inflammatory, and anti-apoptotic activities and display beneficial effects in the management and/or treatment of neurodegenerative disorders in vitro and in vivo. Although a considerable list of compounds is available from , only a few have been evaluated for their neuroprotective potential and still lack information for clinical trials. In this review, the neuroprotective mechanisms and safety profile of extracts/bioactives have been discussed, which might be helpful in the identification of novel potential therapeutic entities in the future.
Topics: Neuroprotective Agents; Cordyceps; Agaricales; Neuroprotection; Adenosine
PubMed: 38201932
DOI: 10.3390/nu16010102 -
Natural Product Reports Jun 2024Covering: 2019 to 2023Nucleoside analogues represent one of the most important classes of small molecule pharmaceuticals and their therapeutic development is... (Review)
Review
Covering: 2019 to 2023Nucleoside analogues represent one of the most important classes of small molecule pharmaceuticals and their therapeutic development is successfully established within oncology and for the treatment of viral infections. However, there are currently no nucleoside analogues in clinical use for the management of bacterial infections. Despite this, a significant number of clinically recognised nucleoside analogues are known to possess some antibiotic activity, thereby establishing a potential source for new therapeutic discovery in this area. Furthermore, given the rise in antibiotic resistance, the discovery of new clinical candidates remains an urgent global priority and natural product-derived nucleoside analogues may also present a rich source of discovery space for new modalities. This Highlight, covering work published from 2019 to 2023, presents a current perspective surrounding the synthesis of natural purine nucleoside antibiotics. By amalgamating recent efforts from synthetic chemistry with advances in biosynthetic understanding and the use of recombinant enzymes, prospects towards different structural classes of purines are detailed.
Topics: Anti-Bacterial Agents; Purine Nucleosides; Biological Products; Molecular Structure; Humans
PubMed: 38197414
DOI: 10.1039/d3np00051f -
Journal of Translational Medicine Oct 2022Abdominal aortic aneurysm (AAA) represents the serious vascular degenerative disorder, which causes high incidence and mortality. Alpha-ketoglutarate (AKG), a crucial...
Abdominal aortic aneurysm (AAA) represents the serious vascular degenerative disorder, which causes high incidence and mortality. Alpha-ketoglutarate (AKG), a crucial metabolite in the tricarboxylic acid (TCA) cycle, has been reported to exert significant actions on the oxidative stress and inflammation. However, its role in AAA still remains elusive. Herein, we examined the effects of AKG on the formation of AAA. The study established an elastase-induced mouse abdominal aortic aneurysms model as well as a TNF-α-mediated vascular smooth muscle cells (VSMCs) model, respectively. We displayed that AKG pre-treatment remarkably prevented aneurysmal dilation assessed by diameter and volume and reduced aortic rupture. In addition, it was also observed that AKG treatment suppressed the development of AAA by attenuating the macrophage infiltration, elastin degradation and collagen fibers remodeling. In vitro, AKG potently decreased TNF-α-induced inflammatory cytokines overproduction, more apoptotic cells and excessive superoxide. Mechanistically, we discovered that upregulation of vpo1 in AAA was significantly suppressed by AKG treatment. By exploring the RNA-seq data, we found that AKG ameliorates AAA mostly though inhibiting oxidative stress and the inflammatory response. PXDN overexpression neutralized the inhibitory effects of AKG on ROS generation and inflammatory reaction in MOVAS. Furthermore, AKG treatment suppressed the expression of p-ERK1/2, 3-Cl Tyr in vivo and in vitro. ERK activator disrupted the protective of AKG on TNF-α-induced VSMCs phenotypic switch. Conclusively, AKG can serve as a beneficial therapy for AAA through regulating PXDN/HOCL/ERK signaling pathways.
Topics: Animals; Aortic Aneurysm, Abdominal; Collagen; Cytokines; Deoxyribonucleosides; Disease Models, Animal; Elastin; Inflammation; Ketoglutaric Acids; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pancreatic Elastase; Purine Nucleosides; Reactive Oxygen Species; Signal Transduction; Superoxides; Tricarboxylic Acids; Tumor Necrosis Factor-alpha
PubMed: 36209172
DOI: 10.1186/s12967-022-03659-2 -
Molecular Therapy : the Journal of the... May 2021The tumor microenvironment (TME), controlled by intrinsic mechanisms of carcinogenesis and epigenetic modifications, has, in recent years, become a heavily researched... (Review)
Review
The tumor microenvironment (TME), controlled by intrinsic mechanisms of carcinogenesis and epigenetic modifications, has, in recent years, become a heavily researched topic. The TME can be described in terms of hypoxia, metabolic dysregulation, immune escape, and chronic inflammation. RNA methylation, an epigenetic modification, has recently been found to have a pivotal role in shaping the TME. The N-methylation of adenosine (mA) modification is the most common type of RNA methylation that occurs in the N-position of adenosine, which is the primary internal modification of eukaryotic mRNA. Compelling evidence has demonstrated that mA regulates transcriptional and protein expression through splicing, translation, degradation, and export, thereby mediating the biological processes of cancer cells and/or stromal cells and characterizing the TME. The TME also has a crucial role in the complicated regulatory network of mA modifications and, subsequently, influences tumor initiation, progression, and therapy responses. In this review, we describe the features of the TME and how the mA modification modulates and interacts with it. We also focus on various factors and pathways involved in mA methylation. Finally, we discuss potential therapeutic strategies and prognostic biomarkers with respect to the TME and mA modification.
Topics: Adenosine; Biomarkers, Tumor; Disease Progression; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Tumor Microenvironment
PubMed: 33839323
DOI: 10.1016/j.ymthe.2021.04.009