Nucleotide inhibitors

Adenylyl Cyclases. Table 4 Nucleotide inhibitors of adenylyl cyclase. Enzyme source and assay conditions were as for Table 3. Values obtained for 3 -ATP are overestimations due to the formation of 2 3 -cAMP from 3 -ATP that occurs nonenzymatically in the presence of divalent cation... 

Shim JH, Hong Z, Wu JZ (2006) Recent patents on nucleoside and nucleotide inhibitors for HCV, Recent Patents Anti-Infect Drug Disc 1 323-331... 

Gorczyca, W.A., Van Hooser, J.P., and Palczewski, K. (1994). Nucleotide inhibitors and activators of retinal guanylyl cyclase. Biochemistry 33 3217-3222. 

Vivet-Boudou V, DidierjeanJ, Isel C, Marquet R. Nucleoside and nucleotide inhibitors of HIV-1 replication. Cell Mol Life Sci. 2006 63 163-186. 

Enhanced Affinity of Nucleotide Inhibitors with Anionic Nitrogenous Rings 66... 

Unanticipated by Crick was the existence of an enz3ane capable of copying RNA into DNA - reverse transcriptase. HIV reverse transcriptase (RT) copies the HIV genomic RNA into a DNA duplex which is subsequently inserted into the human host s DNA. HTV RT is the target of many anti-AIDS drugs, including AZT and many non-nucleotide inhibitors such as nevirapine. 

If the human enzyme is not saturated with glutamine, variations in glutamine concentrations would be expected to affect the rate of purine biosynthesis, although less exquisitely than variations in concentrations of PP-ribose-P. The kinetics of the amidotransferase reaction are hyperbolic with respect to glutamine at all levels of PP-ribose-P, in the presence or absence of nucleotide inhibitors [47,63]. Purine ribonucleotide inhibition is non-competitive with respect to glutamine [47,63] and glutamine does not reverse the association of amidotransferase subunits caused by ribonucleotides [48]. 

Crystallographic and NMR studies of pancreatic RNase have shown that the pyrimidine nucleotide inhibitors, such as 2, (3 )5-iodo UMP,... 

In contrast to DNA pol substrate analogs, non-nucleotide inhibitors (NNI) of DNA-dependent DNA polymerases are potentially able to specifically interact with different regions on DNA pol surface. They can be competitive in relation to the dNTP binding site (in this case we can talk about nucleotide mimics), bind to DNA template binding area and directly prevent initial DNA interaction, have allosteric binding site and, thus, exhibit non-competitive type of inhibition. 

Non-nucleotide pol inhibitors have been discovered among different classes of namral and synthetic chemical compounds. The main of them are long-chain fatty acids, fatty acid derivatives, bile acid derivatives, steroid derivatives, triterpenoids, cerebrosides, alkaloids, flavonoids, anthocyanins, glycolipids, catechins, coenzyme Qs, isosteviols, dipeptide alcohols, vitamins, etc. [52, 53]. The most well-studied non-nucleotide inhibitors are presented in Table 4.2. 

As opposed to nucleotide ones, the lion s share of known non-nucleotides inhibitors are inhibitors of eukaiyotic DNA polymerases. In turn, most of them are inhibitors of animal pol (3. Discovered non-nucleotide inhibitors are characterized by different selectivity with respect to different polymerases. Selectivity can reveal... 

Besides of eukaryotic pols, non-nucleotide inhibitors are known for DNA pols from viruses. Non-nucleotide inhibitors of viral pols are presented by few classes of compounds. So, the 4-oxo-dihydroquinoline-3-carboxamides (4-oxo-DHQ) demonstrated inhibition of HCMV, HSV, and VZV polymerases in subnanomolar concentrations [91, 92]. High specificity for viral DNA polymerases compared to human pols a, y and 5 is observed. 4-Oxo-DHQs are inactive against umelated DNA or RNA vimses, indicating specificity for herpesvirases. A strong correlation between the inhibition of viral DNA polymerases and the antiviral activity for this class of compounds supports inhibition of the viral DNA polymerase as the mechanism of antiviral activity. The 4-oxo-DHQs were found to be competitive inhibitors of nucleoside binding [107]. 

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