Review

Authors: Sohita Dhillon

A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.

Topics: Administration, Oral; Adult; Canada; Clinical Trials as Topic; Decitabine; Drug Approval; Drug Combinations; Drug Development; History, 21st Century; Humans; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; United States; United States Food and Drug Administration; Uridine

PubMed: 32860582
DOI: 10.1007/s40265-020-01389-7

Authors: Jia Ye, Zhihui Jin, Sen Chen...

Osteoarthritis (OA) is a degenerative disease of extremely high incidence in the elderly. Therefore, anti-aging may be an important prerequisite for treating OA. The senescence of chondrocytes and mesenchymal stem cells (MSCs) is one of the important factors that causes OA. Here, the effect of uridine (which is a functional food derived from plants or animals) on senescence of chondrocytes and MSCs was evaluated in and experiments. For this, we established the senescence model of chondrocyte and MSCs , and established the OA model , and a series of experiments (such as CLSM, ELISA, Western blot, etc.) were conducted to evaluate the effect of uridine on chondrocyte and MSCs senescence. The results showed that uridine could alleviate chondrocyte and MSCs senescence by evaluating a series of aging markers. Furthermore, uridine could also relieve OA . In summary, in the present work, we found that uridine can alleviate chondrocyte and MSCs senescence in and experiments. Uridine has shown great potential in the treatment of OA , suggesting that uridine could be used to treat and prevent OA induced by aging, and has potential clinical applications in future.

Topics: Aging; Animals; Cellular Senescence; Chondrocytes; Mesenchymal Stem Cells; Osteoarthritis; Uridine

PubMed: 34974808
DOI: 10.1080/15384101.2021.2010170

Authors: Anne Wilson, Elisa Laurenti, Gabriela Oser...

Bone marrow hematopoietic stem cells (HSCs) are crucial to maintain lifelong production of all blood cells. Although HSCs divide infrequently, it is thought that the entire HSC pool turns over every few weeks, suggesting that HSCs regularly enter and exit cell cycle. Here, we combine flow cytometry with label-retaining assays (BrdU and histone H2B-GFP) to identify a population of dormant mouse HSCs (d-HSCs) within the lin(-)Sca1+cKit+CD150+CD48(-)CD34(-) population. Computational modeling suggests that d-HSCs divide about every 145 days, or five times per lifetime. d-HSCs harbor the vast majority of multilineage long-term self-renewal activity. While they form a silent reservoir of the most potent HSCs during homeostasis, they are efficiently activated to self-renew in response to bone marrow injury or G-CSF stimulation. After re-establishment of homeostasis, activated HSCs return to dormancy, suggesting that HSCs are not stochastically entering the cell cycle but reversibly switch from dormancy to self-renewal under conditions of hematopoietic stress.

Topics: Adult Stem Cells; Animals; Antigens, Differentiation; Bone Marrow; Bromouracil; Fluorouracil; Green Fluorescent Proteins; Hematopoietic Stem Cells; Homeostasis; Mice; Mice, Transgenic; Uridine

PubMed: 19062086
DOI: 10.1016/j.cell.2008.10.048

Authors: Nasrin S Munia, Mohammed M Alanazi, Youness El Bakri...

Nucleoside analogs are frequently used in the control of viral infections and neoplastic diseases. However, relatively few studies have shown that nucleoside analogs have antibacterial and antifungal activities. In this study, a fused pyrimidine molecule, uridine, was modified with various aliphatic chains and aromatic groups to produce new derivatives as antimicrobial agents. All newly synthesized uridine derivatives were analyzed by spectral (NMR, FTIR, mass spectrometry), elemental, and physicochemical analyses. Prediction of activity spectra for substances (PASS) and in vitro biological evaluation against bacteria and fungi indicated promising antimicrobial capability of these uridine derivatives. The tested compounds were more effective against fungal phytopathogens than bacterial strains, as determined by their in vitro antimicrobial activity. Cytotoxicity testing indicated that the compounds were less toxic. In addition, antiproliferative activity against Ehrlich ascites carcinoma (EAC) cells was investigated, and compound (2',3'-di--cinnamoyl-5'--palmitoyluridine) demonstrated promising anticancer activity. Their molecular docking against (1RXF) and (3000) revealed notable binding affinities and nonbonding interactions in support of this finding. Stable conformation and binding patterns/energy were found in a stimulating 400 ns molecular dynamics (MD) simulation. Structure-activity relationship (SAR) investigation indicated that acyl chains, CH(CH)CO-, (CH)C-, and CHCHCO-, combined with deoxyribose, were most effective against the tested bacterial and fungal pathogens. Pharmacokinetic predictions were examined to determine their ADMET characteristics, and the results in silico were intriguing. Finally, the synthesized uridine derivatives demonstrated increased medicinal activity and high potential for future antimicrobial/anticancer agent(s).

Topics: Humans; Molecular Structure; Uridine; Molecular Docking Simulation; Nucleosides; Anti-Infective Agents; Anti-Bacterial Agents; Bacteria; Antineoplastic Agents

PubMed: 37374310
DOI: 10.3390/medicina59061107

Review

Authors: Christine A Arbour, Barbara Imperiali

Nucleoside derivatives, in particular those featuring uridine, are familiar components of the nucleoside family of bioactive natural products. The structural complexity and biological activities of these compounds have inspired research from organic chemistry and chemical biology communities seeking to develop novel approaches to assemble the challenging molecular targets, to gain inspiration for enzyme inhibitor development and to fuel antibiotic discovery efforts. This review will present recent case studies describing the total synthesis and biosynthesis of uridine natural products, and de novo synthetic efforts exploiting features of the natural products to produce simplified scaffolds. This research has culminated in the development of complementary strategies that can lead to effective uridine-based inhibitors and antibiotics. The strengths and challenges of the juxtaposing methods will be illustrated by examining select uridine natural products. Moreover, structure-activity relationships (SAR) for each natural product-inspired scaffold will be discussed, highlighting the impact on inhibitor development, with the aim of future uridine-based small molecule expansion.

Topics: Anti-Bacterial Agents; Biological Products; Drug Discovery; Enzyme Inhibitors; Humans; Molecular Structure; Phosphates; Polyprenols; Structure-Activity Relationship; Uridine

PubMed: 32828427
DOI: 10.1016/j.bmc.2020.115661

Authors: Isabelle Adant, Matthew Bird, Bram Decru...

INTRODUCTION

Primary mitochondrial diseases (PMD) are a large, heterogeneous group of genetic disorders affecting mitochondrial function, mostly by disrupting the oxidative phosphorylation (OXPHOS) system. Understanding the cellular metabolic re-wiring occurring in PMD is crucial for the development of novel diagnostic tools and treatments, as PMD are often complex to diagnose and most of them currently have no effective therapy.

OBJECTIVES

To characterize the cellular metabolic consequences of OXPHOS dysfunction and based on the metabolic signature, to design new diagnostic and therapeutic strategies.

METHODS

In vitro assays were performed in skin-derived fibroblasts obtained from patients with diverse PMD and validated in pharmacological models of OXPHOS dysfunction. Proliferation was assessed using the Incucyte technology. Steady-state glucose and glutamine tracing studies were performed with LC-MS quantification of cellular metabolites. The therapeutic potential of nutritional supplements was evaluated by assessing their effect on proliferation and on the metabolomics profile. Successful therapies were then tested in a in vivo lethal rotenone model in zebrafish.

RESULTS

OXPHOS dysfunction has a unique metabolic signature linked to an NAD+/NADH imbalance including depletion of TCA intermediates and aspartate, and increased levels of glycerol-3-phosphate. Supplementation with pyruvate and uridine fully rescues this altered metabolic profile and the subsequent proliferation deficit. Additionally, in zebrafish, the same nutritional treatment increases the survival after rotenone exposure.

CONCLUSIONS

Our findings reinforce the importance of the NAD+/NADH imbalance following OXPHOS dysfunction in PMD and open the door to new diagnostic and therapeutic tools for PMD.

Topics: Animals; Metabolome; Mitochondrial Diseases; NAD; Oxidative Phosphorylation; Pyruvic Acid; Rotenone; Uridine; Zebrafish

PubMed: 35772644
DOI: 10.1016/j.molmet.2022.101537

Review

Authors: Xueyi Bai, Ding Huang, Pan Xie...

Uridine is one of the essential nutrients in organisms. To maintain normal cell growth and intracellular metabolism, the uridine must be maintained at certain concentration. Recent studies have shown that uridine can reduce inflammatory response in organisms, participate in glycolysis, and regulate intracellular protein modification, such as glycosylation and acetylation. Furthermore, it can protect cells from hypoxic injury by reducing intracellular oxidative stress, promoting high-energy compounds synthesis. Previous studies have shown that the protective effects of uridine are closely related to its effect on mitochondria. This review summarizes the effect of uridine on mitochondrial function.

Topics: Uridine; Mitochondria

PubMed: 37805847
DOI: 10.13345/j.cjb.220899

Authors: Sharmistha Pal, Jakub P Kaplan, Huy Nguyen...

Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pyrimidine biosynthesis pathway. A clinical stage inhibitor of DHODH (rate-limiting enzyme in the de novo pathway) diminishes uridine-5'-phosphate (UMP) pools, generates DNA damage, and induces apoptosis through suppression of replication forks-an "on-target" effect, as shown by uridine rescue. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.

Topics: Animals; Glioma; Humans; Mice; Pyrimidines; Uridine

PubMed: 35985342
DOI: 10.1016/j.ccell.2022.07.012

Review

Authors: Caroline de Almeida, Hélène Scheer, Anthony Gobert...

RNA uridylation consists of the untemplated addition of uridines at the 3' extremity of an RNA molecule. RNA uridylation is catalysed by terminal uridylyltransferases (TUTases), which form a subgroup of the terminal nucleotidyltransferase family, to which poly(A) polymerases also belong. The key role of RNA uridylation is to regulate RNA degradation in a variety of eukaryotes, including fission yeast, plants and animals. In plants, RNA uridylation has been mostly studied in two model species, the green algae and the flowering plant Plant TUTases target a variety of RNA substrates, differing in size and function. These RNA substrates include microRNAs (miRNAs), small interfering silencing RNAs (siRNAs), ribosomal RNAs (rRNAs), messenger RNAs (mRNAs) and mRNA fragments generated during post-transcriptional gene silencing. Viral RNAs can also get uridylated during plant infection. We describe here the evolutionary history of plant TUTases and we summarize the diverse molecular functions of uridylation during RNA degradation processes in plants. We also outline key points of future research.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'.

Topics: Arabidopsis; Chlamydomonas reinhardtii; Plants; RNA; RNA Interference; RNA Stability; Uridine

PubMed: 30397100
DOI: 10.1098/rstb.2018.0163

Review

Authors: Inna Aphasizheva, Ruslan Aphasizhev

RNA editing is a process that alters DNA-encoded sequences and is distinct from splicing, 5' capping, and 3' additions. In 30 years since editing was discovered in mitochondria of trypanosomes, several functionally and evolutionarily unrelated mechanisms have been described in eukaryotes, archaea, and viruses. Editing events are predominantly post-transcriptional and include nucleoside insertions and deletions, and base substitutions and modifications. Here, we review the mechanism of uridine insertion/deletion mRNA editing in kinetoplastid protists typified by Trypanosoma brucei. This type of editing corrects frameshifts, introduces translation punctuation signals, and often adds hundreds of uridines to create protein-coding sequences. We focus on protein complexes responsible for editing reactions and their interactions with other elements of the mitochondrial gene expression pathway.

Topics: Gene Expression Regulation; Holoenzymes; Mitochondria; Protozoan Proteins; RNA Editing; RNA, Protozoan; Trypanosoma brucei brucei; Uridine

PubMed: 26572691
DOI: 10.1016/j.pt.2015.10.004