Authors: Josefine Amalie Loft, Peter Theut Riis, Nicolai Aagaard Schultz...

Cytomegalovirus infection (CMV) can be fatal for organ transplant recipients as shown in this case report. Maribavir is a recently approved drug, which can be used for therapy-refractory CMV infection or when other treatment options cannot be used. The patient in this case report was a CMV-infected liver transplant recipient, who developed a severe erythema and high CMV DNA during valganciclovir therapy. Toxic epidermal necrolysis was suspected. The patient was treated with maribavir, and both CMV DNA and the skin normalised. This case illustrates that maribavir is a useful alternative to other antiviral drugs for CMV infection.

Topics: Humans; Cytomegalovirus Infections; Liver Transplantation; Antiviral Agents; Ribonucleosides; Benzimidazoles; Male; Middle Aged; Cytomegalovirus; Dichlororibofuranosylbenzimidazole

PubMed: 38708697
DOI: 10.61409/V11230726

Review

Authors: Raymund R Razonable

Cytomegalovirus (CMV) infection is arguably the most important infectious complication that negatively affects the outcome of solid organ transplantation. For decades, CMV management after transplantation has relied on antiviral drugs that inhibit viral DNA polymerase (ganciclovir, foscarnet, and cidofovir). However, their use has been complicated by myelosuppression, nephrotoxicity, and selection of drug-resistant viruses. During the past few years, the therapeutic armamentarium for the management of CMV in solid organ transplant recipients has expanded with the approval of letermovir for CMV prophylaxis in high-risk CMV D+/R- kidney recipients, and maribavir for the treatment of refractory and resistant CMV infection. Both drugs offer significant improvement when compared to standard anti-CMV therapies; letermovir was as efficacious for CMV prevention, whereas maribavir was more effective in treating refractory and resistant CMV infections. Both letermovir and maribavir have favorable safety profiles compared to CMV DNA polymerase inhibitors, without the risk of neutropenia and leukopenia associated with ganciclovir and renal toxicities associated with foscarnet and cidofovir. Moreover, letermovir and maribavir are orally bioavailable, which allows convenient outpatient treatment. However, letermovir and maribavir have a significant drug interaction potential in solid organ transplant recipients, resulting in higher levels of calcineurin inhibitors (cyclosporine and tacrolimus) and mTOR inhibitors (sirolimus and everolimus). Both letermovir and maribavir are CMV-specific and do not have clinical efficacy against other herpes viruses. Thus, there is a need for additional antiviral drugs to prevent herpes simplex and other herpes viruses when clinically indicated. This article provides a comprehensive review of the clinical data supporting the use of letermovir and maribavir in clinical practice. The author provides perspectives on the role of these newly approved drugs in the current management landscape of CMV infection in solid organ transplantation.

Topics: Humans; Cytomegalovirus Infections; Antiviral Agents; Ribonucleosides; Organ Transplantation; Acetates; Quinazolines; Benzimidazoles; Cytomegalovirus; Dichlororibofuranosylbenzimidazole

PubMed: 39258274
DOI: 10.2147/DDDT.S265644

Review

Authors: Leonid A Shaposhnikov, Svyatoslav S Savin, Vladimir I Tishkov...

Ribonucleoside hydrolases are enzymes that catalyze the cleavage of ribonucleosides to nitrogenous bases and ribose. These enzymes are found in many organisms: bacteria, archaea, protozoa, metazoans, yeasts, fungi and plants. Despite the simple reaction catalyzed by these enzymes, their physiological role in most organisms remains unclear. In this review, we compare the structure, kinetic parameters, physiological role, and potential applications of different types of ribonucleoside hydrolases discovered and isolated from different organisms.

Topics: Hydrolases; Ribonucleosides; Fungi; Yeasts

PubMed: 37759775
DOI: 10.3390/biom13091375

Authors: Paulina H Wanrooij, Andrei Chabes

The building blocks for RNA and DNA are made in the cytosol, meaning mitochondria depend on the import and salvage of ribonucleoside triphosphates (rNTPs) and deoxyribonucleoside triphosphates (dNTPs) for the synthesis of their own genetic material. While extensive research has focused on mitochondrial dNTP homeostasis due to its defects being associated with various mitochondrial DNA (mtDNA) depletion and deletion syndromes, the investigation of mitochondrial rNTP homeostasis has received relatively little attention. In this issue of the EMBO Journal, Grotehans et al provide compelling evidence of a major role for NME6, a mitochondrial nucleoside diphosphate kinase, in the conversion of pyrimidine ribonucleoside diphosphates into the corresponding triphosphates. These data also suggest a significant physiological role for NME6, as its absence results in the depletion of mitochondrial transcripts and destabilization of the electron transport chain (Grotehans et al, 2023).

Topics: Ribonucleotides; Mitochondria; DNA, Mitochondrial; Nucleotides; Ribonucleosides

PubMed: 37548337
DOI: 10.15252/embj.2023114990

Review

Authors: Phillip J McCown, Agnieszka Ruszkowska, Charlotte N Kunkler...

The chemical identity of RNA molecules beyond the four standard ribonucleosides has fascinated scientists since pseudouridine was characterized as the "fifth" ribonucleotide in 1951. Since then, the ever-increasing number and complexity of modified ribonucleosides have been found in viruses and throughout all three domains of life. Such modifications can be as simple as methylations, hydroxylations, or thiolations, complex as ring closures, glycosylations, acylations, or aminoacylations, or unusual as the incorporation of selenium. While initially found in transfer and ribosomal RNAs, modifications also exist in messenger RNAs and noncoding RNAs. Modifications have profound cellular outcomes at various levels, such as altering RNA structure or being essential for cell survival or organism viability. The aberrant presence or absence of RNA modifications can lead to human disease, ranging from cancer to various metabolic and developmental illnesses such as Hoyeraal-Hreidarsson syndrome, Bowen-Conradi syndrome, or Williams-Beuren syndrome. In this review article, we summarize the characterization of all 143 currently known modified ribonucleosides by describing their taxonomic distributions, the enzymes that generate the modifications, and any implications in cellular processes, RNA structure, and disease. We also highlight areas of active research, such as specific RNAs that contain a particular type of modification as well as methodologies used to identify novel RNA modifications. This article is categorized under: RNA Processing > RNA Editing and Modification.

Topics: High-Throughput Nucleotide Sequencing; Humans; Hydrogen Bonding; Mass Spectrometry; Metabolic Networks and Pathways; Nucleic Acid Conformation; RNA Processing, Post-Transcriptional; Ribonucleosides; Sequence Analysis, RNA; Structure-Activity Relationship

PubMed: 32301288
DOI: 10.1002/wrna.1595

Review

Authors: David M Burger, Laura Nijboer, Mira Ghobreyal...

Letermovir and maribavir have demonstrated efficacy in the prevention and treatment, respectively, of immunosuppressed patients with cytomegalovirus (CMV) infection and disease. These patients often have polypharmacy making them at risk for drug-drug interactions. Both letermovir and maribavir can be perpetrators and victims of drug-drug interactions. Letermovir is a moderate inhibitor of CYP3A, CYP2C8 and OATP1B1/3, and a moderate inducer of CYP2C19. It is a substrate of UGT1A1/3, BCRP, P-gp and OATP1B1/3. Maribavir is a moderate CYP2C9 inhibitor and a substrate of CYP3A. Drug-drug interactions between these anti-CMV agents and a number of therapeutic classes, such as immunosuppressants, antifungal agents, and hemato-oncological agents, can have clinical consequences and deserve dose modification or close monitoring. In a number of examples, three-way drug interactions need to be assessed. The objective of this review is to provide clinicians with guidance for drug-drug interaction management, based on existing data from drug-drug interaction studies, and extrapolation to other relevant co-medications that have not (yet) been studied but that are frequently used in these patient populations.

Topics: Drug Interactions; Humans; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Ribonucleosides; Acetates; Quinazolines; Dichlororibofuranosylbenzimidazole

PubMed: 39509076
DOI: 10.1007/s40262-024-01437-5

Review

Authors: Brian M Maas, Julie Strizki, Randy R Miller...

Molnupiravir is an oral prodrug of the broadly active, antiviral ribonucleoside analog N-hydroxycytidine (NHC). The primary circulating metabolite NHC is taken up into cells and phosphorylated to NHC-triphosphate (NHC-TP). NHC-TP serves as a competitive substrate for viral RNA-dependent RNA polymerase (RdRp), which results in an accumulation of errors in the viral genome, rendering virus replication incompetent. Molnupiravir has demonstrated activity against SARS-CoV-2 both clinically and preclinically and has a high barrier to development of viral resistance. Little to no molnupiravir is observed in plasma due to rapid hydrolysis to NHC. Maximum concentrations of NHC are reached at 1.5 h following administration in a fasted state. The effective half-life of NHC is 3.3 h, reflecting minimal accumulation in the plasma following twice-daily (Q12H) dosing. The terminal half-life of NHC is 20.6 h. NHC-TP exhibits a flatter profile with a lower peak-to-trough ratio compared with NHC, which supports Q12H dosing. Renal and hepatic pathways are not major routes of elimination, as NHC is primarily cleared by metabolism to uridine and cytidine, which then mix with the endogenous nucleotide pools. In a phase III study of nonhospitalized patients with COVID-19 (MOVe-OUT), 5 days of treatment with 800 mg molnupiravir Q12H significantly reduced the incidence of hospitalization or death compared with placebo. Patients treated with molnupiravir also had a greater reduction in SARS-CoV-2 viral load and improved clinical outcomes, compared with those receiving placebo. The clinical effectiveness of molnupiravir has been further demonstrated in several real-world evidence studies. Molnupiravir is currently authorized or approved in more than 25 countries.

Topics: Humans; Translational Science, Biomedical; Cytidine; Ribonucleosides; Hydroxylamines; SARS-CoV-2

PubMed: 38593352
DOI: 10.1111/cts.13732

Authors: Jong Woo Bae, Sangtae Kim, V Narry Kim...

RNA-protein interaction can be captured by crosslinking and enrichment followed by tandem mass spectrometry, but it remains challenging to pinpoint RNA-binding sites (RBSs) or provide direct evidence for RNA-binding. To overcome these limitations, we here developed pRBS-ID, by incorporating the benefits of UVA-based photoactivatable ribonucleoside (PAR; 4-thiouridine and 6-thioguanosine) crosslinking and chemical RNA cleavage. pRBS-ID robustly detects peptides crosslinked to PAR adducts, offering direct RNA-binding evidence and identifying RBSs at single amino acid-resolution with base-specificity (U or G). Using pRBS-ID, we could profile uridine-contacting RBSs globally and discover guanosine-contacting RBSs, which allowed us to characterize the base-specific interactions. We also applied the search pipeline to analyze the datasets from UVC-based RBS-ID experiments, altogether offering a comprehensive list of human RBSs with high coverage (3,077 RBSs in 532 proteins in total). pRBS-ID is a widely applicable platform to investigate the molecular basis of posttranscriptional regulation.

Topics: Amino Acids; Binding Sites; HeLa Cells; Humans; Protein Interaction Domains and Motifs; Proteomics; RNA; RNA-Binding Proteins; Ribonucleosides; Tandem Mass Spectrometry; Thiouridine

PubMed: 34654832
DOI: 10.1038/s41467-021-26317-5

Review

Authors: Ralph E Kleiner

RNA is a central player in biological processes, but there remain major gaps in our understanding of transcriptomic processes and the underlying biochemical mechanisms regulating RNA in cells. A powerful strategy to facilitate molecular analysis of cellular RNA is the metabolic incorporation of chemical probes. In this review, we discuss current approaches for RNA metabolic labeling with modified ribonucleosides and their integration with Next-Generation Sequencing, mass spectrometry-based proteomics, and fluorescence microscopy in order to interrogate RNA behavior in its native context.

Topics: High-Throughput Nucleotide Sequencing; Mass Spectrometry; RNA; Ribonucleosides; Transcriptome

PubMed: 34635895
DOI: 10.1039/d1mo00334h

Review

Authors: Julia Mathlin, Loredana Le Pera, Teresa Colombo...

In the past few years, thorough investigation of chemical modifications operated in the cells on ribonucleic acid (RNA) molecules is gaining momentum. This new field of research has been dubbed "epitranscriptomics", in analogy to best-known epigenomics, to stress the potential of ensembles of RNA modifications to constitute a post-transcriptional regulatory layer of gene expression orchestrated by writer, reader, and eraser RNA-binding proteins (RBPs). In fact, epitranscriptomics aims at identifying and characterizing all functionally relevant changes involving both non-substitutional chemical modifications and editing events made to the transcriptome. Indeed, several types of RNA modifications that impact gene expression have been reported so far in different species of cellular RNAs, including ribosomal RNAs, transfer RNAs, small nuclear RNAs, messenger RNAs, and long non-coding RNAs. Supporting functional relevance of this largely unknown regulatory mechanism, several human diseases have been associated directly to RNA modifications or to RBPs that may play as effectors of epitranscriptomic marks. However, an exhaustive epitranscriptome's characterization, aimed to systematically classify all RNA modifications and clarify rules, actors, and outcomes of this promising regulatory code, is currently not available, mainly hampered by lack of suitable detecting technologies. This is an unfortunate limitation that, thanks to an unprecedented pace of technological advancements especially in the sequencing technology field, is likely to be overcome soon. Here, we review the current knowledge on epitranscriptomic marks and propose a categorization method based on the reference ribonucleotide and its rounds of modifications ("stages") until reaching the given modified form. We believe that this classification scheme can be useful to coherently organize the expanding number of discovered RNA modifications.

Topics: Epigenesis, Genetic; Epigenomics; RNA; RNA Processing, Post-Transcriptional; Ribonucleosides; Transcriptome

PubMed: 32630140
DOI: 10.3390/ijms21134684