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Microbiology Spectrum Mar 2024Porcine reproductive and respiratory syndrome virus (PRRSV) is an RNA virus with constantly emerging recombinant and mutant strains. Because of the high genetic...
UNLABELLED
Porcine reproductive and respiratory syndrome virus (PRRSV) is an RNA virus with constantly emerging recombinant and mutant strains. Because of the high genetic diversity of PRRSV, current vaccines only provide partial protection against the infection of heterologous strains, which makes it a challenge for PRRSV prevention and control. Tubercidin is a naturally extracted compound with potential antiviral properties. However, whether tubercidin has anti-PRRSV ability is unknown. Our study found that tubercidin showed effective antiviral effects on PRRSV replication. In terms of mechanism, tubercidin suppressed PRRSV at the entry, replication, and release steps of the viral life cycle. Additionally, we demonstrated that tubercidin treatment promoted the activation of retinoic acid-inducible gene I and nuclear factor kappa-light-chain-enhancer of activated B cell signaling pathway, thus increasing the type I interferon and inflammatory cytokine expression. Furthermore, tubercidin restrained the viral non-structural protein 2 expression and viral dsRNA synthesis and ultimately inhibited PRRSV replication. Hence, our data showed that tubercidin is promising and has potential antiviral ability against PRRSV replication .
IMPORTANCE
Porcine reproductive and respiratory syndrome (PRRS) is one of the most important swine diseases, which causes huge economic loss worldwide. However, there is no effective therapeutic method for PRRS prevention and control. Here, we found that tubercidin, a naturally extracted adenosine analog, exhibited strong anti-porcine reproductive and respiratory syndrome virus (PRRSV) activity. Mechanically, tubercidin inhibited viral binding, replication, and release. Tubercidin suppressed PRRSV non-structural protein 2 expression, which is important for the formation of replication and transcription complex, leading to the block of viral RNA synthesis and PRRSV replication. Moreover, tubercidin could activate retinoic acid-inducible gene I/nuclear factor kappa-light-chain-enhancer of activated B cell innate immune signaling pathway and increased the expression of interferons and proinflammatory cytokines, which was the other way to inhibit PRRSV replication. Our work evaluated the potential value of tubercidin as an antiviral agent on PRRSV replication and provided a new way to prevent PRRSV replication .
Topics: Swine; Animals; Porcine respiratory and reproductive syndrome virus; NF-kappa B; Porcine Reproductive and Respiratory Syndrome; Tubercidin; Cytokines; DEAD Box Protein 58; Antiviral Agents; Tretinoin
PubMed: 38299833
DOI: 10.1128/spectrum.03479-23 -
Aging Mar 2023
Topics: Animals; Mice; Tubercidin; Aging; Mice, Inbred Strains
PubMed: 36988502
DOI: 10.18632/aging.204625 -
Journal of Cellular and Molecular... May 2022Although small-cell lung cancer (SCLC) accounts for a small fraction of lung cancer cases (~15%), the prognosis of patients with SCLC is poor with an average overall...
Although small-cell lung cancer (SCLC) accounts for a small fraction of lung cancer cases (~15%), the prognosis of patients with SCLC is poor with an average overall survival period of a few months without treatment. Current treatments include standard chemotherapy, which has minimal efficacy and a newly developed immunotherapy that thus far, benefits a limited number of patients. In the current study, we screened a natural product library and identified 5 natural compounds, in particular tubercidin and lycorine HCl, that display prominent anti-SCLC activities in vitro and in vivo. Subsequent RNA-sequencing and functional validation assays revealed the anti-SCLC mechanisms of these new compounds, and further identified new cellular factors such as BCAT1 as a potential therapeutic target with clinical implication in SCLC patients. Taken together, our study provides promising new directions for fighting this aggressive lung cancer.
Topics: Amaryllidaceae Alkaloids; Humans; Immunotherapy; Lung Neoplasms; Phenanthridines; Small Cell Lung Carcinoma; Transaminases; Tubercidin
PubMed: 35318805
DOI: 10.1111/jcmm.17246 -
Virus Research Jan 2024The emergence of new coronaviruses poses a significant threat to animal husbandry and human health. Porcine epidemic diarrhea virus (PEDV) is considered a re-emerging...
The emergence of new coronaviruses poses a significant threat to animal husbandry and human health. Porcine epidemic diarrhea virus (PEDV) is considered a re-emerging porcine enteric coronavirus, which causes fatal watery diarrhea in piglets. Currently, there are no effective drugs to combat PEDV. Drug repurposing screens have emerged as an attractive strategy to accelerate antiviral drug discovery and development. Here, we screened 206 natural products for antiviral activity using live PEDV infection in Vero cells and identified ten candidate antiviral agents. Among them, Tubercidin, a nucleoside analog derived from Streptomyces tubercidicus, showed promising antiviral activity against PEDV infection. Furthermore, we demonstrated that Tubercidin exhibited significant antiviral activity against both classical and variant PEDV. Time of addition assay showed that Tubercidin displayed a significant inhibitory effect on viral post-entry events but not during other periods. Molecular docking analysis indicated that Tubercidin had better docking efficiency and formed hydrophobic interactions with the active pocket of RNA-dependent RNA polymerase (RdRp) of PEDV and other nidoviruses. Additionally, Tubercidin can effectively suppress other porcine nidoviruses, such as SADS-CoV and PRRSV, demonstrating its broad-spectrum antiviral properties. In summary, our findings provide valuable evidence for the antiviral activity of Tubercidin and offer insights into the development of new strategies for the prevention and treatment of coronavirus infections.
Topics: Chlorocebus aethiops; Humans; Animals; Swine; Vero Cells; Tubercidin; Nidovirales; Drug Repositioning; Molecular Docking Simulation; Coronavirus; Coronavirus Infections; Porcine epidemic diarrhea virus; Antiviral Agents; Swine Diseases
PubMed: 38008220
DOI: 10.1016/j.virusres.2023.199275 -
Nature Aging Sep 2022Cellular senescence is a stable type of cell cycle arrest triggered by different stresses. As such, senescence drives age-related diseases and curbs cellular replicative...
Cellular senescence is a stable type of cell cycle arrest triggered by different stresses. As such, senescence drives age-related diseases and curbs cellular replicative potential. Here, we show that 3-deazaadenosine (3DA), an S-adenosyl homocysteinase (AHCY) inhibitor, alleviates replicative and oncogene-induced senescence. 3DA-treated senescent cells showed reduced global Histone H3 Lysine 36 trimethylation (H3K36me3), an epigenetic modification that marks the bodies of actively transcribed genes. By integrating transcriptome and epigenome data, we demonstrate that 3DA treatment affects key factors of the senescence transcriptional program. Remarkably, 3DA treatment alleviated senescence and increased the proliferative and regenerative potential of muscle stem cells from very old mice and . Moreover, 3DA treatment was sufficient to enhance the engraftment of human umbilical cord blood (UCB) cells in immunocompromised mice. Together, our results identify 3DA as a promising drug enhancing the efficiency of cellular therapies by restraining senescence.
Topics: Humans; Mice; Animals; Histones; Cellular Senescence; Tubercidin; Epigenesis, Genetic
PubMed: 36438588
DOI: 10.1038/s43587-022-00279-9 -
Yakugaku Zasshi : Journal of the... 2020RNA interference (RNAi) is the standard method of suppressing gene expression because of its target specificity, potency, and ability to silence the expression of... (Review)
Review
RNA interference (RNAi) is the standard method of suppressing gene expression because of its target specificity, potency, and ability to silence the expression of virtually any gene. Using 21-mer small interfering RNA (siRNA) is the general approach for inducing RNAi, as siRNA can be easily prepared using a DNA/RNA synthesizer. Synthetic siRNA can be chemically modified to increase the potency of RNAi activity and abrogate innate immune stimulation. However, designing chemically modified siRNA requires substantial experimentation. A practical method for understanding the interaction of siRNA and RNAi-related proteins and how modifications affect RNA-protein interactions is therefore needed. Plasmid DNA (pDNA) expressing short hairpin RNA (shRNA) can also be used to induce RNAi. pDNA produces numerous shRNAs that induce RNAi with potent and longterm RNAi activity, even if only one pDNA molecule is delivered to the nucleus. However, this approach has some drawbacks with regard to its therapeutic application, such as a low pDNA transfection efficiency due to its huge molecular size and innate immune responses induced by extra genes, such as CpG motifs. To overcome these issues with RNAi inducers (siRNA and pDNA), our group developed some chemical approaches using chemically modified oligonucleotides. This article focuses on our two original approaches. The first involves the groove modification of siRNA duplexes to understand siRNA-protein interactions using 7-bromo-7-deazaadenosine and 3-bromo-3-deazaadenosine as chemical probes, while the second involves the generation of RNAi medicine using chemically modified DNA, known as an intelligent shRNA expression device (iRed).
Topics: DNA; Drug Development; Immunity, Innate; Oligonucleotides; Protein Interaction Domains and Motifs; RNA Interference; RNA, Small Interfering; RNAi Therapeutics; Tubercidin
PubMed: 32999205
DOI: 10.1248/yakushi.20-00157 -
Marine Drugs Jul 2020The first total synthesis of 5'--α-d-glucopyranosyl tubercidin was successfully developed. It is a structurally unique disaccharide 7-deazapurine nucleoside exhibiting...
The first total synthesis of 5'--α-d-glucopyranosyl tubercidin was successfully developed. It is a structurally unique disaccharide 7-deazapurine nucleoside exhibiting fungicidal activity, and was isolated from blue-green algae. The total synthesis was accomplished in eight steps with 27% overall yield from commercially available 1--acetyl-2,3,5-tri--benzoyl-β-d-ribose. The key step involves stereoselective α--glycosylation of the corresponding 7-bromo-6-chloro-2',3'--isopropylidene-β-d-tubercidin with 2,3,4,6-tetra--benzyl-glucopyranosyl trichloroacetimidate. All spectra are in accordance with the reported data for natural 5'--α-d-glucopyranosyl tubercidin. Meanwhile, 5'--β-d-glucopyranosyl tubercidin was also prepared using the same strategy.
Topics: Carbon-13 Magnetic Resonance Spectroscopy; Models, Chemical; Molecular Structure; Proton Magnetic Resonance Spectroscopy; Tubercidin
PubMed: 32751067
DOI: 10.3390/md18080398 -
Molecules (Basel, Switzerland) Nov 2022Among the scarce validated drug targets against Chagas disease (CD), caused by , the parasite's nucleoside salvage system has recently attracted considerable attention....
Among the scarce validated drug targets against Chagas disease (CD), caused by , the parasite's nucleoside salvage system has recently attracted considerable attention. Although the trypanocidal activity of tubercidin (7-deazapurine) has long been known, the identification of a class of 7-substituted tubercidin analogs with potent in vitro and in vivo activity and much-enhanced selectivity has made nucleoside analogs among the most promising lead compounds against CD. Here, we investigate the recently identified TcrNT2 nucleoside transporter and its potential role in antimetabolite chemotherapy. TcrNT2, expressed in a cell line lacking the NT1 nucleoside transporter locus, displayed very high selectivity and affinity for thymidine with a K of 0.26 ± 0.05 µM. The selectivity was explained by interactions of 2-oxo, 4-oxo, 5-Me, 3'-hydroxy and 5'-hydroxy with the transporter binding pocket, whereas a hydroxy group at the 2' position was deleterious to binding. This made 5-halogenated 2'-deoxyuridine analogues good substrates but 5-F-2'-deoxyuridine displayed disappointing activity against trypomastigotes. By comparing the EC values of tubercidin and its 7-substituted analogues against Cas9, Cas9 and Cas9 it was shown that TcrNT2 can take up tubercidin and, at a minimum, a subset of the analogs.
Topics: Humans; Trypanosoma cruzi; Nucleoside Transport Proteins; Tubercidin; Biological Transport; Chagas Disease; Deoxyuridine
PubMed: 36432150
DOI: 10.3390/molecules27228045 -
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 For Parasitology.... Dec 2021Kinetoplastid parasites are the causative agents of Chagas disease (CD), leishmaniasis and human African trypanosomiasis (HAT). Despite a sustained decrease in the...
Kinetoplastid parasites are the causative agents of Chagas disease (CD), leishmaniasis and human African trypanosomiasis (HAT). Despite a sustained decrease in the number of HAT cases, more efforts are needed to discover safe and effective therapies against CD and leishmaniasis. Kinetoplastid parasites lack the capability to biosynthesize purines de novo and thus critically depend on uptake and processing of purines from host cells. As such, modified purine nucleoside analogues may act as broad-spectrum antikinetoplastid agents. This study assessed the in vitro activity profile of 7-modified 6-methyl tubercidin derivatives against Trypanosoma cruzi, Leishmania infantum, Trypanosoma brucei brucei and T. b. rhodesiense, and led to the identification of analogues that display activity against all these species, such as 7-ethyl (13) and 7-chloro (7) analogues. These selected analogues also proved sufficiently stable in liver microsomes to warrant in vivo follow-up evaluation.
Topics: Antiprotozoal Agents; Humans; Nucleosides; Purines; Structure-Activity Relationship; Trypanosoma brucei brucei; Trypanosoma cruzi
PubMed: 34375904
DOI: 10.1016/j.ijpddr.2021.08.001