• Klíčová slova
• Chemoterapie, Hematologie onkologická,
• MeSH
• farmakoterapie MeSH
• nukleosidy MeSH

An example of a 2′-C-methyl branched nucleoside analogue bearing 3,4-dihydro-3-oxopyrazine-2-carboxamide as the base, namely 4-(2-C-methyl-β-D-ribofuranosyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide, is reported. This compound was synthesized following a Vorbrüggen's glycosylation procedure in a few steps. When evaluated in cell culture experiments against a broad range of viruses, this compound did not exhibit any significant antiviral effect or cytotoxicity.

• MeSH
• antivirové látky MeSH
• biologické jevy MeSH
• hepatitida C MeSH
• nukleosidy MeSH
• viry hepatitidy MeSH

• MeSH
• nukleosidy MeSH
• nukleové kyseliny, nukleosidy a nukleotidy MeSH
• Publikační typ
• sborníky MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• chemie, klinická chemie
• biologie
• biochemie

Acyklická analoga složek nukleových kyselin jsou látky s velmi širokým spektrem účinku. Jejich použití přitom stále naráží na překážky spojené s jejich biologickou dostupností, případně vedlejšími účinky. Tyto problémy byly v minulosti řešeny mimo jiné přípravou různých profarmak. Tento článek v kostce představuje výběr použitých strategií, přičemž pozornost je věnována v neposlední řadě biotechnolo- gickým úvahám a postupům v rámci přípravy představených struktur.

Acyclic analogs of nucleic acids components are compounds with a broad spectrum of action. Their use collides with hurdles associated with their biological availability, or with side effects. In the past, these problems were solved for example by preparation of different prodrugs. This paper presents briefly a selection of used strategies, last but not least with respect to the biotechnological reflections and methods on the field of preparation of the presented structures.

• MeSH
• acyklovir farmakokinetika   farmakologie   chemie   MeSH
• adenin analogy a deriváty   MeSH
• antivirové látky * MeSH
• biofarmacie MeSH
• biologická dostupnost * MeSH
• biotechnologie metody   trendy   MeSH
• cytosin analogy a deriváty   MeSH
• farmakogenetika MeSH
• ganciklovir farmakokinetika   farmakologie   chemie   MeSH
• guanin analogy a deriváty   MeSH
• individualizovaná medicína MeSH
• inhibitory reverzní transkriptasy MeSH
• lidé MeSH
• nukleosidy farmakologie   chemie   MeSH
• nukleotidy cyklické farmakologie   chemie   MeSH
• organofosfáty farmakologie   chemie   MeSH
• prekurzory léčiv farmakologie   chemie   terapeutické užití   MeSH
• protinádorové látky * MeSH
• Check Tag
• lidé MeSH

Nucleoside analogs represent the largest class of small molecule-based antivirals, which currently form the backbone of chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. High antiviral potency and favorable pharmacokinetics parameters make some nucleoside analogs suitable also for the treatment of acute infections caused by other medically important RNA and DNA viruses. This review summarizes available information on antiviral research of nucleoside analogs against arthropod-borne members of the genus Flavivirus within the family Flaviviridae, being primarily focused on description of nucleoside inhibitors of flaviviral RNA-dependent RNA polymerase, methyltransferase, and helicase/NTPase. Inhibitors of intracellular nucleoside synthesis and newly discovered nucleoside derivatives with high antiflavivirus potency, whose modes of action are currently not completely understood, have drawn attention. Moreover, this review highlights important challenges and complications in nucleoside analog development and suggests possible strategies to overcome these limitations.

• MeSH
• antivirové látky chemie   farmakologie   MeSH
• Culicidae virologie   MeSH
• Flavivirus účinky léků   MeSH
• infekce viry z rodu Flavivirus farmakoterapie   virologie   MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• nukleosidy chemie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

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

While cidofovir, adefovir and tenofovir are the three acyclic nucleoside phosphonates (ANPs) that have been licensed for clinical use (the latter as a single-, double- and triple-drug combination), there are many more ANPs that await their application for medical or veterinary use: (S)-HPMPA, (S)-HPMPDAP, cPrPMEDAP, (R)-HPMPO-DAPy, PMEO-DAPy, 5-X-PMEO-DAPy, (R)-PMPO-DAPy, (S)-HPMP-5-azaC, and cyclic (S)-HPMP-5-azaC, and alkoxyalkyl prodrugs thereof.

• MeSH
• antivirové látky MeSH
• klinická chemie MeSH
• nukleosidy MeSH
• nukleotidy MeSH
• organofosfonáty MeSH

Nucleoside-based drugs, recognized as purine or pyrimidine analogs, have been potent therapeutic agents since their introduction in 1950, deployed widely in the treatment of diverse diseases such as cancers, myelodysplastic syndromes, multiple sclerosis, and viral infections. These antimetabolites establish complex interactions with cellular molecular constituents, primarily via activation of phosphorylation cascades leading to consequential interactions with nucleic acids. However, the therapeutic efficacy of these agents is frequently compromised by the development of drug resistance, a continually emerging challenge in their clinical application. This comprehensive review explores the mechanisms of resistance to nucleoside-based drugs, encompassing a wide spectrum of phenomena from alterations in membrane transporters and activating kinases to changes in drug elimination strategies and DNA damage repair mechanisms. The critical analysis in this review underlines complex interactions of drug and cell and also guides towards novel therapeutic strategies to counteract resistance. The development of targeted therapies, novel nucleoside analogs, and synergistic drug combinations are promising approaches to restore tumor sensitivity and improve patient outcomes.

• MeSH
• antimetabolity farmakologie   MeSH
• léková rezistence MeSH
• lidé MeSH
• membránové transportní proteiny MeSH
• nádory * farmakoterapie   MeSH
• nukleosidy farmakologie   terapeutické užití   MeSH
• protinádorové látky * farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

A number of structurally diverse nucleoside phosphonic acids have been tested against human recombinant thymidine phosphorylase and human platelets supernatant using 2'-deoxy-5-nitrouridine as the substrate. We have selected several inhibitors working at micromolar level as lead structures for further evaluation.

• MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• křečci praví MeSH
• kyseliny fosforité chemie   MeSH
• lidé MeSH
• nukleosidy chemie   farmakologie   MeSH
• thymidinfosforylasa antagonisté a inhibitory   chemie   MeSH
• trombocyty enzymologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: The review covers basic principles of the prodrug strategy applied to antiviral nucleoside drugs or drug candidates. Specific role of amino acids as promoieties is explained with respect to transport mechanisms, pharmacokinetics and a low toxicity of compounds. Synthetic approaches to the most important representatives (compounds under clinical investigations or available on the market) are described, including valacyclovir, valganciclovir, valomaciclovir stearate, valcyclopropavir, valtorcitabine, valopicitabine and several attempts to amino acid modifications of antiretroviral nucleosides. METHOD: A special attention is paid to acyclic nucleoside phosphonates, where the phosphonic acid residue is esterified with a side-chain hydroxyl group of appropriate amino acid (serine, tyrosine) which can be used as single amino acid or as a part of dipeptides further modified on the terminal carboxyl function. The most advantageous pharmacokinetic profile and the best oral bioavailability were found in tyrosinebased prodrugs. RESULTS & CONCLUSION: Studies were performed successfully on 1-(S)-[3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (cidofovir), 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine and some (R)-2- (phosphonomethoxy)propyl and 2-(phosphonomethoxy)ethyl derivatives including adefovir.

• MeSH
• adenin analogy a deriváty   chemie   farmakologie   MeSH
• antivirové látky chemie   farmakologie   MeSH
• Cytomegalovirus účinky léků   MeSH
• cytosin analogy a deriváty   chemie   farmakologie   MeSH
• lidé MeSH
• nukleosidy chemie   farmakologie   MeSH
• nukleotidy chemie   farmakologie   MeSH
• organofosfonáty chemie   farmakologie   MeSH
• prekurzory léčiv chemie   farmakologie   MeSH
• virus varicella zoster účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH