Nucleoside/nucleotide analogs

Nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide reverse transcriptase inhibitor (NtRI) A modified version of a naturally-occurring nucleoside or nucleotide that prevents human immunodeficiency virus (HIV) replication by interfering with the function of the viral reverse transcriptase enzyme. The nucleoside/nucleotide analog causes early termination of the proviral DNA chain. For activity, an NRTI requires three phosphorylation steps once inside the cell, whereas an NtRI has a phosphate group attached and needs only two phosphorylation steps inside the cell for activity. 

D. The nucleoside/nucleotide analogs like azidothymidine (AZT) and didanosine are incorporated into the DNA synthesized by HIV reverse transcriptase. Because they do not have a 3 -hydroxyl group, they cannot form a bond with the next nucleotide and the chain is terminated. Host cell DNA synthesis is not affected because of the nuclear DNA repair mechanisms. 

The HIV-encoded, RNA-dependent DNA polymerase, also called reverse transcriptase, converts viral RNA into proviral DNA that is then incorporated into a host cell chromosome. Available inhibitors of this enzyme are either nucleoside/nucleotide analogs or nonnucleoside inhibitors. 

However, acyclic nucleotide analogs (acyclic nucleoside phosphonates) have been developed, which carry one phosphonate moiety and require only the two subsequent phosphorylation steps (De Clercq et al. 1978). Independent of virus-encoded kinases, they display a broader spectrum of efficacy. This class comprises important drugs against HIV (tenofovir) and HBV (adefovir, tenofovir), as well as cidofovir, which is approved for use against CMV retinitis, but also displays an exceptionally broad efficacy profile against many herpesviruses, adenovirus, poxviruses, and papillomaviruses (De Clercq and Holy 2005). 

Kalek, M., Jemielity, J., Grudzien, E., Zuberek, J., Bojarska, E., Cohen, L., Stepinski, J., Stolarski, R., Davis, R. E., Rhoads, R. E., and Darzynkiewicz, E. (2005). Synthesis and biochemical properties of novel mRNA S cap analogs resistant to enzymatic hydrolysis. Nucleosides, Nucleotides, and Nucleic Acid 24, 615-621. 

Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine (Figure 49-2). Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. However, only two rather than three intracellular phosphorylations are required for active inhibition of DNA synthesis. 

S Additional information <5, 7, 11, 25> (<5,7,11 > in the absence of nucleoside diphosphates the enzyme undergoes Mg -dependent stoichiometric autophosphorylation using ATP, GTP or y-thiotriphosphate as phosphate donor, 2 mol phosphate per mol enzyme [12] <25> autophosphorylation and phosphorylation of histone Hl [19] <31> strong preference for d-enantiomers of antiviral nucleotide analogs like ddATP, ddCTP, 3 -deoxy-3 -thymidine, 2 ,3 -didehydro-2 ,3 -dideoxythymidine [50]) [12, 19, 50]... 

The nucleoside analogs entecavir and clevudine, the nucleotide analog emtricitabine, and the immunologic modulators theradigm-HBV and thymosin alpha-1 are new agents under evaluation for the treatment of HBV infection. 

Fischhaber, P. L., et al. (1997). Synthesis of duplex DNA containing a spin labeled analog of 2 -deoxycytidine. Nucleosides Nucleotides 16, 365-377. 

Marquez, V. E. (1989) Design, synthesis, and antiviral activity of nucleoside and nucleotide analogs. Nucleotide Analogues Antiviral Agents, ACS Symposium Series 401, pp. 140-155. 

Torii, T., Onishi, T., Izawa, K., et al. (2006) Synthesis of 6-arylthio analogs of 2, 3 -dideoxy-3 -fluoroguanosine and their effect against hepatitis B virus replication. Nucleosides, Nucleotides Nucleic Acids, 25, 655-665. 

Metal ion complexes of antivirally active acyclic nucleoside phosphonates as nucleotide analogs 04CSR191. 

The effect of ara-ATP and ara-CTP on ribonucleotide reduction has also been studied in crude extracts from Novikoff (139) and Ehrlich (140) ascites tumor cells. Inhibition by these nucleotide analogs appeared to be competitive with effector nucleotides, but not with nucleoside diphosphate substrates. 

Under basic conditions (0.2 M barium hydroxide, 100°, 30 minutes), the nucleoside 3 5 -cycIic phosphates are converted into the 3 - and 5 -phosphates in the ratio of about 5 1. For cytidine 3 5 -cyclic phosphate, some concomitant deamination to the uridine nucleotide analogs is also observed (as noted with cytidine 3 -phosphate), so that the nucleotides obtained are similar to those found in the alkaline hydrolyzate of uridine 3 5 -cyclic phosphate. In addition, one of the nucleotides obtained in these hydrolyzates differs from the 3 - or 5 -phosphates in its ion-exchange chromatographic behavior. The presence of an unidentified nucleoside monophosphate in small proportion was also observed when 2 -deoxy-cytidine 3 5 -cyclic phosphate was hydrolyzed with barium hydroxide under similar conditions. 

Synthesis and biological activity of 2- and 6-C-substituted purine bases, nucleosides, and acyclic nucleotide analogs 00CLY978. 

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