Nucleotide Analogues

Figure Bl.17.12. Time-resolved visualization of the dissociation of myosin SI from filamentous actin (see also figure Bl.17.6). Shown are selected filament images before and after the release of a nucleotide analogue (AMPPNP) by photolysis (a) before flashing, (b) 20 ms, (c) 30 ms, (d) 80 ms and (e) 2 s after flashing. Note the change in obvious order (as shown by the diffraction insert in (a)) and the total dissociation of the complex in (e). The scale bar represents 35.4 mn. Picture with the courtesy of Academic Press.

D Abramo CM, Cellai L, Gotte M (2004) Excision of incorporated nucleotide analogue chain-terminators can diminish their inhibitory effects on viral RNA-dependent RNA polymerases. J Mol Biol 337 1-14... 

Dutartre H, Bussetta C, Boretto J, Canard B (2006) General catalytic deficiency of hepatitis C virus RNA polymerase with an S282T mutation and mutually exclusive resistance towards 2 -modified nucleotide analogues. Antimicrob Agents Chemother 50 4161 169 Elferink RO, Groen AK (2002) Genetic defects in hepatobiliary transport. Biochim Biophys Acta... 

The acyclic nucleoside phosphonates (ANPs) can be considered as nucleotide rather than nucleoside analogues, in that, besides the purine or pyrimidine base, they contain an (acyclic) sugar moiety to which a phosphonate is attached. In these nucleotide analogues (Fig. 2), the phosphoric ester grouping (= P-O---C-----) is... 

Appropriately designed prodrugs, for example, phosphonoamidates (Lee et al. 2005), may allow acyclic nucleoside phosphonates such as tenofovir to be specifically targeted at tissues, that is, lymphatic tissue, where the virus (i.e., HIV) replicates. This principle has been recently extended to another nucleotide analogue, GS-9148 (Cmiar et al. 2008) and its phosphonoamidate prodrug, GS-9131 (Ray et al. 2008). 

All the nucleoside (and nucleotide) analogues that have entered the clinic for the treatment of HBV infections (i.e., nucleoside analogues lamivudine, entecavir, tel-bivudine nucleotide analogues adefovir and tenofovir) are fairly well tolerated without side effects that would preclude their long-term usage. The nucleoside analogues in (pre)clinical development for the treatment of HCV infections are not yet sufficiently advanced to assess their tolerability and/or safety. 

Coelmont L, Paeshuyse J, Windisch MP, De Clercq E, Bartenschlager R, Neyts J (2006) Ribavirin antagonizes the in vitro anti-hepatitis C virus activity of 2 -C-methylcytidine, the active component of valopicitabine. Antimicrob Agents Chemother 50 3444-3446 D Abramo CM, Cellai L, GOtte M (2004) Excision of incorporated nucleotide analogue chain-terminators can diminish their inhibitory effects on viral RNA-dependent RNA polymerases. J Mol Biol 337 1-14... 

A few studies have evaluated standard lFN-a2a and -a2b combined with lamivudine, whereas more recent trials tested pegylated IFN-a combined with nucleo-side/nucleotide analogues. The aim was to determine whether combination therapy... 

Koning H. de. Pandit UK Unconventional nucleotide analogues VI. Rec. Trav. Chim. 1971 91 1069-1080. 

The potential clinical utility of the bDNA assay in AIDS patients was demonstrated by monitoring CMV DNA levels in the blood of a patient undergoing gan-cilovir therapy (Chemoff et al 1997), in semen specimens from patients being treated with the antiviral nucleotide analogue cidofovir (Lalezari et al 1995), and in cerebrospinal fluid from patients with CMV neurologic infections (Flood et ai, 1997). These studies demonstrate that bDNA can be used to measure CMV DNA in various clinical specimens. To date, no comparisons of bDNA with other strategies for detection of CMV DNA in clinical specimens have been published. 

Lalezari, J. P etal. (1995). (S)-l-[3-Hydroxy-2-(phosphonylmethosy)propyl]cytosine (cidofovir) Results of a phase I/n study of a novel antiviral nucleotide analogue. J. Infect. Dis. 171,788-798. 

The antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine also uses its N7 as a major binding site and forms a N7-phosphonate macrochelate (698).1833 Another antiviral analogue of 2 -deoxyguanosine, acyclovir (9-[(2-hydroxyethoxy)-methyl]guanine) forms with Ni11 a bis-complex with two N7 coordinated in trans position to each other.1834... 

Shoji A, Hasegawa T, Kuwahara M et al (2007) Chemico-enzymatic synthesis of a new fluorescent-labeled DNA by PCR with a thymidine nucleotide analogue bearing an acridone derivative. Bioorg Med Chem Lett 17 776-779... 

Kers, A. and Stawinski, J., A new type of nucleotide analogue with 4-py-ridylphosphonate internucleotide linkage, Tetrahedron Lett., 40, 4263, 1999. 

NMR investigations of some carbohydrate-substituted tetrazolo[l,5-h]pyrimidin-5(6//)ones as nucleotide analogues have been studied by Chu et al. <1997JOC7267>. The H and 13C chemical shifts of these derivatives are shown in Table 3. 

The Fe-protein has the protein fold and nucleotide-binding domain of the G-protein family of nucleotide-dependent switch proteins, which are able to change their conformation dependent on whether a nucleoside diphosphate (such as GDP or ADP) is bound instead of the corresponding triphosphate (GTP or ATP). However, nucleotide analogues, which induce the conformational switch of the Fe-protein, do not allow substrate reduction by the MoFe-protein, nor does reduction of the MoFe-protein by other electron-transfer reagents (whether small proteins or redox dyes) drive substrate reduction. Only the Fe-protein can reduce the MoFe-protein to a level that allows it to reduce substrates such as... 

Martin JC (1989) Nucleotide Analogues as Antiviral Agents, ACS Symp. Ser. 401, Washington... 

Adefovir (Hepsera) [Antiviral/Acyclic Nucleotide Analogue]... 

C) Lamivudine is a cytosine nucleoside analogue efavirenz is an adenosine nucleotide analogue. 

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