cytidine analog Dotaz Zobrazit nápovědu
BACKGROUND: Trichomonas vaginalis is the causative agent of a sexually transmitted disease in humans. The virulence of the parasite depends on multiple factors, including the presence of endosymbiotic dsRNA viruses. The presence of Trichomonasviruses (TVV) was associated with more severe genital symptoms, increased proinflammatory host reactions, and modulated parasite sensitivity to metronidazole. However, no efficient antiviral drugs are available against TVV to derive isogenic TVV-positive and TVV-negative cell lines that are essential for investigations of the TVV impact on T. vaginalis biology. METHODS: 7-Deaza-2'-C-methyladenosine (7d2CMA) and 2'-C-methylcytidine (2CMC) were used for TVV inhibitory assay. TVV replication was monitored using quantitative reverse transcription PCR (RT qPCR) and western blotting. Modeling of TVV1 RNA-dependent RNA polymerase (RdRp) was performed to visualize the inhibitor-RdRp interaction. Susceptibility to metronidazole was performed under aerobic and anaerobic conditions. RESULTS: We demonstrated that 2CMC but not 7d2CMA is a potent inhibitor of TVV replication. Molecular modeling suggested that the RdRp active site can accommodate 2CMC in the active triphosphate nucleotide form. The effect of 2CMC was shown on strains infected with a single and multiple TVV species. The optimal 2CMC concentration (10 μM) demonstrated strong selectivity for TVVs over trichomonad growth. The presence of TVV has no effect on T. vaginalis metronidazole susceptibility in derived isogenic cell lines. CONCLUSIONS: 2CMC acts against TVVs and represents a new inhibitor against Totiviridae viruses. Our isogenic clones are now available for further studies of various aspects of T. vaginalis biology related to TVV infection.
- MeSH
- antivirové látky farmakologie MeSH
- cytidin farmakologie MeSH
- lidé MeSH
- metronidazol farmakologie MeSH
- nukleosidy farmakologie MeSH
- paraziti * MeSH
- RNA-dependentní RNA-polymerasa MeSH
- RNA-viry * genetika MeSH
- Totiviridae * genetika MeSH
- Trichomonas vaginalis * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Tick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series of nucleoside analogues was tested for the ability to inhibit the replication of TBEV in porcine kidney cells and human neuroblastoma cells. The interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. The nucleoside analogues 7-deaza-2'-C-methyladenosine (7-deaza-2'-CMA), 2'-C-methyladenosine (2'-CMA), and 2'-C-methylcytidine (2'-CMC) inhibited TBEV replication. These compounds showed dose-dependent inhibition of TBEV-induced cytopathic effects, TBEV replication (50% effective concentrations [EC50]of 5.1 ± 0.4 μM for 7-deaza-2'-CMA, 7.1 ± 1.2 μM for 2'-CMA, and 14.2 ± 1.9 μM for 2'-CMC) and viral antigen production. Notably, 2'-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC50] of ∼50 μM). The anti-TBEV effect of 2'-CMA in cell culture diminished gradually after day 3 posttreatment. 7-Deaza-2'-CMA showed no detectable cellular toxicity (CC50 > 50 μM), and the antiviral effect in culture was stable for >6 days posttreatment. Computational molecular analyses revealed that compared to the other two compounds, 7-deaza-2'-CMA formed a large cluster near the active site of the TBEV polymerase. High antiviral activity and low cytotoxicity suggest that 7-deaza-2'-CMA is a promising candidate for further investigation as a potential therapeutic agent in treating TBEV infection.
- MeSH
- adenosin analogy a deriváty chemie farmakologie MeSH
- antivirové látky chemie farmakologie MeSH
- buněčné linie MeSH
- cytidin analogy a deriváty chemie farmakologie MeSH
- lidé MeSH
- nukleosidy chemie farmakologie MeSH
- prasata MeSH
- replikace viru účinky léků MeSH
- tubercidin analogy a deriváty chemie farmakologie MeSH
- viry klíšťové encefalitidy účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- buněčné linie MeSH
- cytosinnukleotidy farmakologie MeSH
- fibroblasty MeSH
- interferony biosyntéza farmakologie MeSH
- kultivační techniky MeSH
- kuřecí embryo MeSH
- L buňky (buněčná linie) účinky léků MeSH
- nukleosidy farmakologie MeSH
- nukleotidy farmakologie MeSH
- polynukleotidy farmakologie MeSH
- virus vezikulární stomatitidy, kmen Indiana MeSH
- zvířata MeSH
- Check Tag
- kuřecí embryo MeSH
- zvířata MeSH
Hlavnou zložkou extraktov Ophiocordyceps sinensis a Cordyceps militaris sú polysacharidy. Ide o prírodné biopolyméry, ktoré predstavujú veľkú triedu biologicky aktívnych zložiek. Tie prispievajú k ich farmakologickej aktivite a pôsobeniu na zdravie. Obsahujú monosacharidy, ktoré zahŕňajú ramnózu, ribózu, arabinózu, xylózu, manózu, glukózu, galaktózu, manitol, fruktózu a sorbózu. Exopolysacharidová frakcia má veľký počet farmakologických účinkov, z ktorých dva najdôležitejšie sú imunomodulačné a protinádorové. Medzi obsahové polysacharidy patrí tiež manoglukán vykazujúci slabú cytotoxickú aktivitu proti rakovinovej bunkovej línii SPC-I1). Z Ophiocordyceps sinensis sa postupne izolovalo viac ako desať nukleozidov a im príbuzných zlúčenín vrátane adenínu, adenozínu, inozínu, cytidínu, cytozínu, guanínu, uridínu, tymidínu, uracilu, hypoxantínu a guanozínu. Obsahuje mnoho aminokyselín a polypeptidov, u ktorých sa predpokladá, že by mohli mať vplyv na kardiovaskulárny systém. Taktiež vykazujú sedatívny a hypnotický účinok, pričom najúčinnejšou zložkou spomedzi nich je tryptofán. Polysacharidy sa extrahovali zo štyroch vzoriek: vzorka 1 (pestovaná na substráte Oryza sativa indica, kmeň Ophiocordyceps sinensis), vzorka 2 (pestovaná na substráte Oryza sativa japonica, kmeň Ophiocordyceps sinensis), vzorka 3 (pestovaná na substráte Oryza sativa indica, kmeň Cordyceps militaris), vzorka 4 (pestovaná na substráte Oryza sativa japonica, kmeň Cordyceps militaris). Prostredníctvom NMR spektroskopie a následným porovnaním s literatúrou sa podarilo zistiť, že majoritná chemická zlúčenina v deproteinizovaných extraktoch 1 a 4 bol hydrofilný polyglukán označovaný ako CBHP2).
The main component of Ophiocordyceps sinensis and Cordyceps militaris extracts are polysaccharides. These are natural biopolymers that represent a large class of biologically active components. These contribute to their pharmacological activity and effect on health. They contain monosaccharides that include rhamnose, ribose, arabinose, xylose, mannose, glucose, galactose, mannitol, fructose, and sorbose. The exopolysaccharide fraction has a large number of pharmacological effects, the two most important of which are immunomodulatory and antitumour. Among the contained polysaccharides is also mannoglucan, which shows weak cytotoxic activity against the SPC-I1) cancer cell line. More than ten nucleosides and their related compounds, including adenine, adenosine, inosine, cytidine, cytosine, guanine, uridine, thymidine, uracil, hypoxanthine, and guanosine, have been successively isolated from Ophiocordyceps sinensis. It contains many amino acids and polypeptides that are thought to affect the cardiovascular system. They also have a sedative and hypnotic effect, with tryptophan being the most effective component among them. Polysaccharides were extracted from four samples: sample 1 (grown on the substrate Oryza sativa indica, strain Ophiocordyceps sinensis), sample 2 (grown on the substrate Oryza sativa japonica, strain Ophiocordyceps sinensis), sample 3 (grown on the substrate Oryza sativa indica, strain Cordyceps militaris), sample 4 (grown on Oryza sativa japonica substrate, strain Cordyceps militaris). Through NMR spectroscopy and subsequent comparison with the literature, the majority of a chemical compound in deproteinized extracts 1 and 4 was found to be a hydrophilic polyglucan referred to as CBHP2).
- Klíčová slova
- GEMCITABINE (ELI LILLY),
- MeSH
- antitumorózní látky aplikace a dávkování farmakologie MeSH
- deoxycytidin analogy a deriváty MeSH
- lidé MeSH
- míra přežití MeSH
- nemalobuněčný karcinom plic farmakoterapie MeSH
- nukleosidy aplikace a dávkování terapeutické užití MeSH
- příznaky a symptomy farmakoterapie MeSH
- Check Tag
- lidé MeSH
