Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the sensitivity of various cellular and viral DNA polymerases to Suramin, an antitrypanosomal drug, which has been reported to exhibit antireverse transcriptase activity. We find that Suramin is a nonspecific inhibitor of all the viral and cellular DNA polymerases, including terminal deoxynucleotidyl transferase, and that the inhibition is most readily reversed by the addition of serum albumin. The drug appears to bind to all the enzyme proteins with no apparent selectivity. Binding of Suramin to enzyme has been found to result in the loss of both substrate and templateprimer binding abilities of various enzymes, confirming the nonspecific nature of protein-Suramin interaction.
 ...
PMID:Observations on the suramin-mediated inhibition of cellular and viral DNA polymerases. 240 17

1 We have investigated increases in cytosolic Ca(2+) in response to nucleotides in mixed rat cerebrocortical cultures (neurons and glia in similar numbers) and in essentially neuron-free glial cultures. 2 In both cultures, the agonist-response profile was 2-methylthioADP(2MeSADP)>2-methylthioATP(2MeSATP)>ADP>ATP>adenosine 5'-O-(3-thiotriphosphate), consistent with a P2Y(1) receptor. The maximal responses to 2MeSADP, 2MeSATP and ADP were identical, but that to ATP was higher. 3 Suramin, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid, reactive blue 2 (RB2), and adenosine biphosphate (A3P5P) were antagonists with apparent pA(2) values of 5.5 for suramin, 6.4 for RB2, and 4.7 for A3P5P. 4 Single cell imaging divided the cells from the mixed neuronal-glial cultures into two populations: responsive (neurons) and unresponsive (glial cells) to high [K(+)]. The response of cells to nucleotides was almost exclusively limited to those not responsive to high K(+). 5 In the presence of extracellular Mn(2+), the response of the mixed cultures to 30 mM K(+) and 20 micro M Bay K 8644 was attenuated. However, when 2MeSADP was added there was no reduction in response in cultures previously loaded with Mn(2+). This further indicated that the 2MeSADP response was not in the neurons. 6 Reverse transcriptase-polymerase chain reaction studies detected transcripts for P2Y(1), P2Y(4) and P2Y(6) in RNA preparations from embryonic rat cortex, and from both mixed and glial cultures. P2Y(2) transcripts were not detected in the embryonic cortex. 7 Based on this and previous work, it is proposed that the principal P2Y influences in the brain are on cytosolic Ca(2+) in glial cells and presynaptic sites on neurons.
 ...
PMID:P2Y receptor regulation of cultured rat cerebral cortical cells: calcium responses and mRNA expression in neurons and glia. 1277 Sep 33

Caliciviridae are RNA viruses with a single-stranded, positively oriented polyadenylated genome, responsible for a broad spectrum of diseases such as acute gastroenteritis in humans. Recently, analyses on the structures and functionalities of the RNA-dependent RNA polymerase (RdRp) from several Caliciviruses have been reported. The RdRp is predicted to play a key role in genome replication, as well as in synthesis and amplification of additional subgenomic RNA. Starting from the crystal structures of human Norovirus (hNV) RdRp, we performed an in silico docking search to identify synthetic compounds with predicted high affinity for the enzyme active site. The best-ranked candidates were tested in vitro on murine Norovirus (MNV) and hNV RdRps to assay their inhibition of RNA polymerization. The results of such combined computational and experimental screening approach led to the identification of two high-potency inhibitors: Suramin and NF023, both symmetric divalent molecules hosting two naphthalene-trisulfonic acid heads. We report here the crystal structure of MNV RdRp alone and in the presence of the two identified inhibitors. Both inhibitory molecules occupy the same RdRp site, between the fingers and thumb domains, with one inhibitor head close to residue 42 and to the protein active site. To further validate the structural results, we mutated Trp42 to Ala in MNV RdRp and the corresponding residue (i.e., Tyr41 to Ala) in hNV RdRp. Both NF023 and Suramin displayed reduced inhibitory potency versus the mutated hNV RdRp, thus hinting at a conserved inhibitor binding mode in the two polymerases.
 ...
PMID:Structure-based inhibition of Norovirus RNA-dependent RNA polymerases. 2244 84