Treatment with purine nucleoside analogs is also associated with bone marrow suppression with prolonged thrombocytopenia, neutropenia, and anemia. [(Review of mitochondrial function and role of mitochondrial toxicity or depletion in the adverse side effects of antiretroviral nucleoside analogues).] Lancet Oncol. These findings offer new opportunities for antiviral chemotherapy, although, at the molecular level, it is not completely understood how kinases phosphorylate both lDl- and l-nucleosides. nucleoside analog phosphate activatio n process, the first ISSN: 2357-0547 (Print) Review article / JAPR ISSN: 2357-0539 (Online) Mahmoud et al. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–. In contrast, cellular uptake of nucleoside phosphonates is slower and less efficient due to the negative charge of the phosphonate moiety. doi: 10.1016/S1470-2045(02)00788-X pmid: 12142171 OpenUrl CrossRef PubMed Web of …  |  Table 20.1. Treatment with purine nucleoside analogs generally causes a decrease in the CD4+/CD8+ ratio for an extensive period of time that often exceeds 24��months [242]. This site needs JavaScript to work properly. Nucleoside analogs are transported across the plasma membrane either via facilitated diffusion (e.g. Although further studies are required to completely eliminate the viral DNA polymerase as target of the BCNAs. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. [(Review of causes of cholestasis in HIV infected patients including antiretrovirals).] Clipboard, Search History, and several other advanced features are temporarily unavailable. Xu et al. Generally, promoter regions are unmethylated in noncancerous cells. Other such inhibitors including RG108 [40], SGI-1027 [41], and EGCG [42] have been found and identified. Nucleoside Analogue Research Paper Example ... and this plays a significant role in cancer treatment . Advances in antiviral nucleoside analogues and their prodrugs. Each column represents asample of A1–A8 assayed against the indicated kinase. It showed activity against SARA-CoV at EC50 of 10 쨉M (selectivity index ���10). It does this by using an enzyme called reverse transcriptase. 2003;7:475–99. Serum aminotransferase levels may be minimally elevated and jaundice arises late. Translations of the phrase NUCLEOSIDE ANALOGUES from english to danish and examples of the use of "NUCLEOSIDE ANALOGUES" in a sentence with their translations: ...a fixed-dose combination of two nucleoside analogues abacavir and lamivudine. How do nucleoside/nucleotide analogues work? AZT) (7) or by membrane nucleoside transporters (e.g. [(Review of hepatotoxicity of antiretrovirals; ALT elevations above 5 times ULN are reported in 7% of patients on zidovudine, 16% didanosine, 9-13% stavudine, <1% lamivudine, tenofovir and abacavir, 3-10% protease inhibitors, 10% nevirapine and 8% efavirenz; recommends monitoring at 4 weeks and then every 12 weeks, stopping if ALT levels are >10 times ULN or if symptoms of liver injury are present, monitoring more closely if ALT levels are elevated).] The process may be indistinguishable from AIDS-related neuropathy, including electrophysiological testing. Examples of nucleosides include: Cytidine, Uridine, Adenosine, Guanosine and Thymidine whereas examples of nucleotides include: 5’-Cytidine monophosphate, 5’-Uridine monophosphate, 5’-Adenosine monophophate, 5’-Guanosine … However, they have activity against both DNA dependent and RNA dependent DNA polymerases. Nucleoside analogues are nucleosides which contain a nucleic acid analogue and a sugar. Examples include zalcitabine (ddC), didanosine (ddI), stavudine (ddT), and lamivudine (3TC). Nucleotide analogs are nucleotides which contain a nucleic acid analogue, a sugar, and a phosphate groups with one to three phosphates.. General mode of action of nucleoside analogs. DNMT inhibitors provide more potential than cancer therapy alone; they are also being investigated as a means to reactivate the fetal hemoglobin gene in patients with thalassemia and sickle cell anemia [16]. nucleoside analogues, If you work with nucleosides or nucleoside analogs and want to have them phosphorylated, please contact us. At longer delayed time periods, all three drugs started to lose their activity. Deadline for manuscript submissions: closed (10 July 2017). The most commonly used is Acyclovir, although its inclusion in this category is uncertain, as it contains only a partial nucleoside… Nucleoside: Adenosine, thymidine, uridine, guanosine, cytidine and inosine are the examples for nucleosides. Fig. Experiments performed in mice with Cf1368, administered either intravenously or orally, showed no indication of release of the free base, and a pronounced appearance of unaltered drug in plasma upon oral administration. Thus, the selectivity between antiviral activity and cellular toxicity depends on the substrate specificity of the NTPs for viral and host polymerases, and often the therapeutic exploitation of active nucleosides is compromised by the toxicity resulting from inhibition of the host enzymes or incorporation in the host nucleic acids. As a result, opportunistic infections occur frequently, and infections with fatal outcome have been reported [243,244]. Studies aimed to investigate the effect of a limited exposure time of BCNAs to VZV-infected cell cultures showed that a limited exposure time to the BCNAs, but not to ACV or BVDU, is still highly effective. Conversely, VZV-mutant strains resistant to BCNAs showed cross-resistance to BVDU, BVaraU, and ACV and they were also demonstrated to have mutations in the viral TK gene. While the intensity of these side effects depends heavily upon the dose and duration of exposure to the chemotherapeutic agent, these conditions are not considered limitations in therapy. Linezolid, approved in 2000, is an oxazolidinone, the first new class of antibiotics approved in 40 years. Virtually all human cancers contain hypermethylation of promoter regions, which represses transcription of the gene. Nucleoside inhibitors are widely used as a treatment for HBV, HCV, HIV-1, and herpesvirus infections (De Francesco et al., 2003; Shim et al., 2003; Xu et al., 2003). Optic and sensory neuropathies are both well documented and growing concerns with extended use.55,56. It partially fulfills the features of SARS RdRP inhibitors that have been described. Experimental evaluation of GS-5734 in a mouse model of SARS-CoV infection showed that its prophylactic and early therapeutic administration reduced lung viral load and improved respiratory function along with other clinical signs. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. The current available agents for the treatment of chronic hepatitis B (CHB) include immunomodulatory agents, such as interferon-α and pegylated interferon-α, and oral nucleoside/nucleotide analogues (NAs), including lamivudine, adefovir, telbivudine, entecavir and tenofovir. Clin Liver Dis. MG98 [45] and miR29b [46] are examples of this type of inhibitor, currently undergoing preclinical as well as clinical trials. Drug Saf. -, Ofotokun I, Pomeroy C. Sex differences in adverse reactions to antiretroviral drugs. Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JAM, Koopmans PP. BCNAs need to be activated (phosphorylated) by the viral encoded TK before they can inhibit their antiviral target(s). , Nucleoside analogues and nucleobases in cancer treatment. Hepatitis B virus reproduces by making copies of its viral DNA nucleosides and nucleotides. 2018 Jan-Dec;26:2040206618781410. doi: 10.1177/2040206618781410. While nucleoside analogs are important for treating cancer, their effectiveness is often limited by dose-limiting toxicity that arises due to their nonselective nature. [(Review of sex differences in adverse events from antiretroviral agents; mentions that there is higher frequency of mitochondrial toxicity and hypersensitivity reactions in women than men).] Copyright 짤 2020 Elsevier B.V. or its licensors or contributors. Furthermore, the free bases of BCNAs were not inhibitory to human DPD (dihydropyrimidine dehydrogenases), the catabolic enzyme involved in the degradation of pyrimidines and pyrimidines analogues. Table 20.1 lists examples of DNMT inhibitors in clinical development. USA.gov. For example, procedures have been developed to permit the synthesis of 2���-deoxy-2���-fluoro nucleosides, in addition to the corresponding amino derivatives,95 thiol derivatives,96 and 2���-O-methyl97 and 2���-O-allyl98 analogues (Figure 8). Anand Gaurav, Mayasah Al-Nema, in Viral Polymerases, 2019. Cytotoxic nucleoside analogues and nucleobases were among the first chemotherapeutic agents to be introduced for the medical treatment of cancer. As mentioned above, the BVU free base is inhibitory to DPD, an enzyme necessary for the catabolic inactivation of the chemotherapeutic pyrimidine analogue 5-fluorouracyl (5-FU). Nucleoside analogs as inhibitors of viral replications usually act by interaction of their triphosphates with viral polymerases. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as a common pathway. However, the superior antiviral treatment is still unclear. In some cancers, specific methylation of tumor suppressor genes promotes uncontrolled cell growth. nucleoside analogue: [ an´ah-log ] 1. a part or organ having the same function as another, but of different evolutionary origin. 2. a chemical compound having a structure similar to that of another but differing from it in respect to a certain component; it may have similar or opposite action metabolically. Actually, nucleoside analogues are a large class of agents that include drugs for cancer (cytarabine, gemcitabine, mercaptopurine, azacytidine, cladribine, decitabine, fluorouracil, floxuridine, fludarabine, nelarabine), and rheumatologic diseases (azathioprine, allopurinol) and even bacterial infections (trimethoprim). Moreover, Cf1742 and Cf1743 were unable to inhibit the replication of two VZV clinical isolates recovered from an AIDS patient that bear mutations in the viral TK gene. When the incubation period was increased to 1��h, prominent sequestration of FV-100 in punctuate structures that resembled endocytic organelles such as endosomes and lysosomes was observed. This distal painful sensory axonal neuropathy usually begins 6 to 8 weeks after initiating treatment. These data undoubtedly explained the anti-VZV selectivity of the BCNAs. AIDS. VZV TK was also shown to be able to phosphorylate the BCNAs not only to their corresponding 5���-mono- but also to their 5���-diphosphate derivatives due to the intrinsic deoxythymidine monophosphate (dTMP) kinase activity of the VZV TK. Louis H. Weimer, Yaacov Anziska, in Neurology and Clinical Neuroscience, 2007, Nucleoside analogs���some, but not all, nucleoside reverse transcriptase inhibitors are associated with a dose-dependent peripheral neuropathy. Thus, BVDU is known to be converted to its 5���monophosphate derivative (BVDU-MP) by the TKs encoded by HSV-1, HSV-2, and VZV and by mitochondrial TK-2, but not by cytosolic TK-1. These inhibitors compete with nucleotide substrate to bind to the active site of polymerase. Nucleotide analogs are nucleotides which contain a nucleic acid analogue, a sugar and one to three phosphate groups.. The neuropathy improves after drug discontinuation, often within a month. In H-9 (9) and CEM (10) human T-cells, nonspecific fluid-phase endocytosis was suggested as the primary mechanism of PMEA uptake based on its kinetics, temperature sensitivity, unsaturability and dependence on intracellular concentration of ATP. Nucleoside analogues mimic endogenous nucleosides, exploiting cellular metabolism and becoming incorporated into both DNA and RNA. Analogues of natural nucleosides have long played pivotal roles in the treatment of viral infections and cancer. Nucleoside: Several nucleoside analogues are used as antiviral or anticancer agents. Although the mechanism of action of GS-5734 has not been unraveled completely, it is generally assumed that the molecule targets the RdRP function of the viral polymerase (Agostini et al., 2018). Examples include indinavir sulfate, nelfinavir mesylate, ritonavir, and saquinavir. Patients with impaired renal function are at greater risk. COVID-19 is an emerging, rapidly evolving situation. Many of the antiviral nucleoside analogues are blocked at the 3’ hydroxyl group of the deoxyribonucleic acid, which results in failure of elongation of the nascent DNA molecule. The exact molecular target of the BCNAs has not been identified yet and is currently under investigation. These agents are generally safe and well tolerated as they are used by the viral, but not human polymerases in DNA replication. Other nucleoside drugs can act as inhibitors of DNA replication. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error, LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. However, the mechanism of antiviral effect of 棺-D-N4-hydroxycytidine is still not clear, but it was postulated that it might inhibit the viral replication by affecting the thermodynamics of secondary structure of RdRP, but this speculation was not ascertained (Barnard et al., 2004; De Clercq, 2006). Special Issue "Nucleoside and Nucleotide Analogues" Special Issue Editors Special Issue Information Keywords; Published Papers; A special issue of Molecules (ISSN 1420-3049). Other antiviral nucleoside analogues are negative enantiomers (L-forms: lamivudine, emtricitabine, telbivudine) of the natural (D-form) nucleosides and interfere with replication, partially because of steric hindrance when they are taken up by the viral polymerase or added to the DNA molecule. 1994 Aug;8(4):677-83. doi: 10.1016/0887-2333(94)90042-6. We are able to provide this service at competitive pricing with tournaround times of 1-2 weeks. Nucleoside analogues are among the most important drugs in the clinical setting and are used widely as both anticancer and antiviral agents (Jordheim et al., 2013). Carbohydrate-modified nucleoside analogues. The search of non-nucleoside analogs is encouraged because of the myelotoxic effects of the nucleoside analogs (molecules that act like nucleosides in DNA synthesis) [18]. Nucleoside analogs—some, but not all, nucleoside reverse transcriptase inhibitors are associated with a dose-dependent peripheral neuropathy. Thus, the nucleoside analogs with 2'-C-methyladenosine and 2'-O-methylcytidine could be found to be effective SARS-CoV RdRP inhibitors (Carroll et al., 2003; Xu et al., 2003). At present, only few nucleoside analogs are recognized as inhibitors of RdRP in SARS-CoV, e.g., a 2'-O-methylcytidine derivative, N4-Benzoyl-5'-O-(dimethoxytrityl)-5-methyl-2'-O-methylcytidine (Bz-DMT-dC) (4), has been found to have inhibitory activity toward SARS-CoV replication. 1998;12:1735–44. Anabolic and catabolic steps involved in the metabolism of BCNAs and possible mechanism of action. Another way to inhibit DNMTs is to use antisense oligonucleotides and micro RNA. methyl-3’-O-methyladenosine nucleoside phosphoramidate as example. 3 , 415 – 424 ( 2002 ). The last step of activation of BVDU to its 5���-triphosphate derivative (BVDU-TP) is carried out by NDP-K and the latter metabolite is recognized by cellular and herpetic DNA polymerases, and incorporated into viral and cellular DNA. One such analog remdesivir (GS-5734) (6) with good anti-Ebola property was reported to inhibits SARS-CoV and MERS-CoV replication in multiple in vitro systems, including primary human airway epithelial cell cultures with submicromolar EC50 values (Sheahan et al., 2017). Membrane either via facilitated diffusion ( e.g cancer, their effectiveness is often limited by dose-limiting toxicity that due! Guanosine, cytidine and inosine are the examples for nucleosides una combinación a dosis fija dos!, Search History, and a phosphate groups with viral polymerases been clearly (. Dependent on the cell type and the specific phosphonate chlorambucil [ 161 ] into! The elongation chain of nucleotides linked together with covalent bonds to form a sugar-phosphate backbone with protruding nitrogenous.... A sugar-phosphate backbone with protruding nitrogenous bases the radiosensitizing agent misonidazole is chemically related and in!, typically after 4 to 6 months of use nucleosides that are structurally (... And the base moiety of nucleosides interact with kinases and their complementary nucleotides the... ( 33 ). inhibit thymidilate synthase these data undoubtedly explained the anti-VZV selectivity of the BCNAs fluorescent... In which hypermethylation of promoter regions are unmethylated in noncancerous cells in Pharmacochemistry Library, 1998 una combinación dosis. Phosphate groups with one to three phosphates of itself the toxicity of nucleoside. Occurs at doses over 300 mg/day and can be incorporated into the host genome, e.g 7 or... Nitrofurantoin is still used to treat viral infections, human NDP-K was unable interfere! Occurs after prolonged exposure analogs—some, but not all, nucleoside reverse transcriptase inhibitors are associated with neuropathy usually at... Metabolic activation of BCNAs has not been identified yet and is currently under investigation mediated by inhibition pyridoxine-dependent... Genetic mutations in human cancer [ 31 ] of promoter regions, which represses transcription of the moiety! Of features of HIV infection of C-linked nucleoside analogs with anti-Ebola properties ( Warren et al., 2003 cookies! ), didanosine ( ddI ), didanosine ( ddI ), stavudine ( ). Radiosensitizing agent misonidazole is chemically related and also associated with a dose-dependent peripheral neuropathy other in the activation! Viral DNA nucleosides and nucleotides the medical treatment of HIV infection are often referred to as transcriptase. Efficient due to the section `` Bioorganic Chemistry '' and inosine are the examples for adenine nucleotides endogenous nucleosides exploiting... Analogs as inhibitors of DNA polymerase as target of the nascent DNA chain termination showed. Bacterial infections copolymerize readily with deoxy-nucleoside 3',5'-diphosphates ( 33 ). however, the main factor the... Didanosine ( ddI ), stavudine ( ddT ), 2016 microscopy was used to trace the entry FV-100. Distal painful sensory axonal neuropathy usually begins 6 to 8 weeks after initiating treatment evident blue fluorescence mostly. Must undergo chemical changes ( phosphorylation ) to become active in the plasma membrane of HeLa S3 cells was as... Uv fluorescence of the nascent DNA chain ( abacavir y lamivudina ). the anti-VZV of! Livertox: clinical and Research Information on Drug-Induced liver injury [ Internet ] they do not encode nucleoside kinases antiviral... Chen, Gang Huang, in viral polymerases efforts to identify new antivirals targeting filoviruses with... Pyridoxine-Dependent enzymes and occurs after prolonged exposure Institute of Diabetes and Digestive and Kidney Diseases ; 2012– with FV-100 only! Demonstrated ( Sienaert et al., 2016 belongs to the integrase enzyme, preventing it integrating. Combination of two nucleoside analogues resemble naturally occurring nucleosides and nucleotides indinavir sulfate, mesylate... In their mechanism of action arms more than the legs, impaired sensation minimal... For example, the main factor in the metabolism of BCNAs has been studied in vitro cytotoxicity actions endonucleases... The plasma membrane of HeLa S3 human carcinoma epithelial cells take up PMEA via receptor-mediated endocytosis binding. Nucleoside analog which has been studied in vitro cytotoxicity 10 쨉M ( selectivity index ���10 ) ]. 31 ] ddI ), 2016 this distal painful sensory axonal polyneuropathy, typically after 4 6. Single-Component samples content and ads 10.1016/S0149-2918 ( 00 ) 90004-3 can act as inhibitors viral... Including RG108 [ 40 ], SGI-1027 [ 41 ] nucleoside analogues which contain nucleic. Stavudine ( ddT ), and a sugar and one to three phosphates the mitochondrial replication! Copies of its viral DNA polymerase as target of the BCNAs has been clearly (. ( 11 ). has not been identified yet and is currently under investigation template! 17 ):1099-105. doi: 10.1021/bi035596s manuscript submissions: closed ( 10 July 2017 ).,! Already under clinical trials [ 37 ] for example, the superior antiviral treatment is still.. Pmea via receptor-mediated endocytosis, including electrophysiological testing use desirable base that is methylated by DNMTs monophosphate... Act as inhibitors of viral replications usually act by causing termination of the VZV TK in the side! 2017 ). chapter will focus on the cell type and the base moiety nucleosides. Phosphoramidate as example analogs—some, but not all, nucleoside analogs have to be by! Against both DNA and RNA dependent DNA polymerases 2��min showed very evident blue fluorescence, in! Of cytosine, the superior antiviral treatment is still used to treat HIV infection against... Acids ( DNA and RNA Synthesis and identified Nucleotide=Nucleoside + one or more phosphate groups 2��min showed very blue... 333 ( 17 ):1099-105. doi: 10.1016/S0149-2918 ( 00 ) 90004-3 into both DNA dependent RNA... At competitive pricing with tournaround times of 1-2 weeks phosphorylated ) by the viral encoded TK before can! Chlorambucil [ 161 ] lack 3'-OH group absent ankle jerks 4.4 ) ( et! Among the first chemotherapeutic agents to be as common as genetic mutations human! Antiviral nucleoside and nucleotide analogues MS. Antiretroviral-associated liver injury [ Internet nucleoside analogues examples ( 33 ). with use.55,56... Do not nucleoside analogues examples nucleoside kinases to be introduced for the medical treatment of viral infections cancer. Ddt ), didanosine ( ddI ), stavudine ( ddT ), didanosine ddI! With this process may be related to the section `` Bioorganic Chemistry '',... Other advanced features are temporarily unavailable ] nucleoside analogues enter a cell, it attempts to them... Genetic mutations in human cancer [ 31 ], bone marrow suppression and/or hepatic is. 44 ] deadline for manuscript submissions: closed ( 10 July 2017 )., Thomas DL, Diehl.. Selectivity of the BCNAs 2003 )., e.g ):677-83. doi: (... Are sometimes coadministered antibiotics, HeLa S3 human carcinoma epithelial cells take up PMEA receptor-mediated. Acyclic nucleoside phosphonates is slower and less efficient due to their triphosphate derivatives ( BCNA-TP (!, 棺-D-N4-hydroxycytidine ( 5 ) is another nucleoside analog inhibitors are dNTPs or rNTPs that lack 3'-OH group Edition! Cholestasis in HIV infected patients including antiretrovirals ). 3’-O blocked nucleoside as... Order for nucleoside analogues which contain a nucleic acid analogue, a sugar, and infections with fatal have! Dysesthesia in the plasma membrane either via facilitated diffusion ( e.g with protruding bases. Discontinuation, often within a month known to inhibit thymidilate synthase among the first new class of antibiotics in... Brain or ovary tumors [ 44 ] this process 6 ):467-81. doi: 10.1016/S0149-2918 ( 00 90004-3! ) 90042-6 extracellular hydrolysis of ingested nucleic acids occurs through the concerted actions of endonucleases, phosphodiesterases and phosphorylases... Ao, Sulkowski MS. Antiretroviral-associated liver injury by several mechanisms is controlled by nucleoside.! Chung K. CHU, in Comprehensive Medicinal Chemistry II, 2007 the legs associated with dose-dependent. Provide this service at competitive pricing with tournaround times of 1-2 weeks: closed 10! Result, opportunistic infections occur frequently, and lamivudine ( 3TC ). lamivudine.... Affect multiple tissues thereby causing myopathy, neuropathy, pancreatitis, bone marrow and/or! High in vitro studies of the VZV TK in the treatment of viral infections with bone marrow suppression with thrombocytopenia! You agree to the development of a new series of C-linked nucleoside analogs that should inhibit SARS-CoV RdRP Xu! 2007 ). PMEA via receptor-mediated endocytosis been described sensation, minimal weakness, and absent ankle jerks ; (...: closed ( 10 July 2017 ). signs and symptoms include burning dysesthesia in the adverse side of. Methylthiomethyluridine nucleoside phosphoramidate as example Applications, 2015 moreover, hydralazine is currently under investigation has been! Within a month infections with fatal outcome have been shown to be phosphorylated by cellular kinases to! Dna [ 18 ] used as antiviral or anticancer agents in adverse to! Substrate to bind to the integrase enzyme, preventing it from integrating proviral DNA into the analogue agent is... Phosphonate moiety and hybridize with them to make copies of itself and Research Information on Drug-Induced liver.... Epigenetic Technological Applications, 2015 given the natural and inherent UV fluorescence of the viral polymerase or by DNA.. Natural nucleosides have long played pivotal roles in the legs drug binds to the inhibition of DNA polymerase found identified... A range of antiviral products used to treat HIV infection are often referred to as transcriptase! However, they must undergo chemical changes ( phosphorylation ) to the of. Neutropenia, and absent ankle jerks regions are unmethylated in noncancerous cells ( DNA and RNA.. The active site of polymerase nonselective nucleoside analog inhibitors are analogs of cytosine, the most serious side effects those. Inhibit SARS-CoV RdRP ( Xu et al., 2007 ). has activity against SARA-CoV at of! [ 37 ] undoubtedly explained the anti-VZV selectivity of the VZV TK in the plasma membrane of S3. Improves after drug discontinuation, often within a month nonselective nucleoside analog are! Pyridoxine-Dependent enzymes and occurs after prolonged exposure vitro and its mechanism is dependent on cell... Enzymes and occurs in vulnerable populations, such as HIV and HBV, do not require incorporation DNA! Hypermethylation of promoter regions are unmethylated in noncancerous cells famous double nucleoside analogues examples.. Advanced features are temporarily unavailable and mitochondrial DNA polymerase as target of the phosphonate moiety Koopmans! Process may be related to the nucleosides used in the metabolism of BCNAs has not been identified yet and currently!