Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Influence of water solutions of chemically pure adaptogen--synthetic analog of Rhodiola Rosea extract phenol composition (SAR) on functional activity of hemopoietic and tumor cells of mice with Ehrlich ascite cancer was studied in vitro. The periodical character of SAR effects was shown to be different for both types of cells, and at 1 x 10(-2) and 1 x 10(-26) M concentrations simultaneous stimulation of blood marrow cells colony-forming activity and inhibition of the latter in tumor elements was revealed. Essential changes of reactions of both cell types after adding the DNA-dependent RNA polymerase blocker Actinomycin D permit to suggest SAR effects to be connected with drug influence on the membrane RNA of the target cells.
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PMID:[Mechanism of differential effect of low dose adaptogens on the functional activity of normal and transformed cellular elements in vitro]. 179 47

Interphase chromatin is arranged into topologically separated domains comprising gene expression and replication units through genomic sequence elements, so-called MAR or SAR regions (for matrix- or scaffold-associating regions). S/MAR regions are located near the boundaries of actively transcribed genes and were shown to influence their activity. We show that scaffold attachment factor B (SAF-B), which specifically binds to S/MAR regions, interacts with RNA polymerase II (RNA pol II) and a subset of serine-/arginine-rich RNA processing factors (SR proteins). SAF-B localized to the nucleus in a speckled pattern that coincided with the distribution of the SR protein SC35. Furthermore, we show that overexpressed SAF-B induced an increase of the 10S splice product using an E1A reporter gene and repressed the activity of an S/MAR flanked CAT reporter gene construct in vivo . This indicates an association of SAF-B with SR proteins and components of the transcription machinery. Our results describe the coupling of a chromatin organizing S/MAR element with transcription and pre-mRNA processing components and we propose that SAF-B serves as a molecular base to assemble a 'transcriptosome complex' in the vicinity of actively transcribed genes.
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PMID:SAF-B protein couples transcription and pre-mRNA splicing to SAR/MAR elements. 967 16

RNA polymerase (RNAP) and the DNA template must rotate relative to each other during transcription elongation. In the cell, however, the components of the transcription apparatus may be subject to rotary constraints. For instance, the DNA is divided into topological domains that are delineated by rotary locked boundaries. Furthermore, RNAPs may be located in factories or attached to matrix sites limiting or prohibiting rotation. Indeed, the nascent RNA alone has been implicated in rotary constraining RNAP. Here we have investigated the consequences of rotary constraints during transcription of torsionally constrained DNA by free RNAP. We asked whether or not a newly synthesized RNA chain would limit transcription elongation. For this purpose we developed a method to immobilize covalently closed circular DNA to streptavidin-coated beads via a peptide nucleic acid (PNA)-biotin conjugate in principle mimicking a SAR/MAR attachment. We used this construct as a torsionally constrained template for transcription of the beta-lactamase gene by Escherichia coli RNAP and found that RNA synthesis displays similar characteristics in terms of rate of elongation whether or not the template is torsionally constrained. We conclude that transcription of a natural bacterial gene may proceed with high efficiency despite the fact that newly synthesized RNA is entangled around the template in the narrow confines of torsionally constrained supercoiled DNA.
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PMID:In vitro transcription of a torsionally constrained template. 1180 94

Screening of the in-house sample collection for compounds with HCV NS5B RNA dependent RNA polymerase inhibition led to the identification of a new lead. Afterwards, we discovered that the screening lead, rather than containing the expected structure 1, was comprised of roughly a 1:1 mixture of meconic acid 2 and its monoethyl ester 3, with all inhibitory potency residing with 3. We propose that this compound shares critical common features for activity with alpha,gamma-diketoacids inhibitors previously discovered by our group. SAR around this molecule will be presented to provide an improved basis for structure-based ligand design.
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PMID:The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase. 1514 86

HTS of the compound collection for inhibition of the HCV RNA dependent RNA polymerase identified two 168 member N-acyl pyrrolidine combinatorial mixture hits. Deconvolution and expansion of these mixtures by solid phase synthesis to establish initial SAR and identify a potent inhibitor is reported.
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PMID:Identification of small molecule inhibitors of the hepatitis C virus RNA-dependent RNA polymerase from a pyrrolidine combinatorial mixture. 1574 95

GE23077 is a novel RNA polymerase inhibitor that is isolated from the fermentation broth of an Actinomadura sp. It is a cyclic heptapeptide complex made up of four factors, differing in the structure of acyl group connected to the side chain of an alpha,beta-diaminopropanoic acid moiety and in the configuration of the stereocenter of an alpha-amino-malonic acid residue. Although GE23077 shows strong inhibitory activity on both Rifampicin-sensitive and -resistant polymerases, it exhibits poor antimicrobial activity. The most reasonable explanation for this property has been based on the lack of penetration of the molecule across the bacterial membrane, owing to its strong hydrophilic character. To improve penetration, several parts of the molecule were accordingly modified with the aim of altering the physico-chemical properties of GE23077. The current SAR study has identified moieties important for RNA polymerase activity.
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PMID:Antibiotics GE23077, novel inhibitors of bacterial RNA polymerase. Part 3: Chemical derivatization. 1599 Feb 99

A novel series of selective HCV NS5B RNA dependent RNA polymerase inhibitors has been disclosed. These compounds contain an appropriately substituted tetrahydrobenzothiophene scaffold. This communication will detail the SAR and activities of this series.
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PMID:Tetrahydrobenzothiophene inhibitors of hepatitis C virus NS5B polymerase. 1626 Jan 31

The lack of antiviral compounds targeting flaviviruses represents a significant problem in the development of strategies for treating West Nile Virus (WNV), Dengue, and Yellow Fever infections. Using WNV high-throughput screening techniques developed in our laboratories, we report the identification of several small molecule anti-WNV compounds belonging to four different structural classes including pyrazolines, xanthanes, acridines, and quinolines. The initial set of "hits" was further refined using cell viability-cytotoxicity assays to two 1,3,5-triaryl pyrazoline compounds: 1-(4-chlorophenylacetyl)-5-(4-nitrophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole and 1-benzoyl-5-(4-chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole. On the basis of their activity and favorable therapeutic indexes, these compounds were identified as viable leads and subjected to additional evaluation using an authentic viral titer reduction assay employing an epidemic strain of WNV. The compounds were further evaluated in a transient replicon reporting system to gain insight into the mechanism of action by identifying the step at which inhibition takes place during viral replication. The results indicate the pyrazolines inhibit RNA synthesis, pointing to viral RNA polymerase, RNA helicase, or other viral replication enzymes as potential targets. Progress was also made in understanding the structural requirements for activity by synthesizing a focused chemical library of substituted pyrazolines. Preliminary SAR data are presented that show the aryl-rings are required for activity against WNV. More importantly, the results indicate WNV activity is tolerant to aryl-substitutions paving the way for the design and development of much larger combinatorial libraries with varied physicochemical properties.
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PMID:Identification of compounds with anti-West Nile Virus activity. 1653 2

In a routine screening of our small-molecule compound collection we recently identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study based on 35 analogues suggests ways in which the pharmacophore could be further optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics studies with the lead compound and X-ray crystallography of an inhibitor-CDK2 complex demonstrated that its mode of inhibition is competitive. Functional kinase assays confirmed the selectivity toward CDKs, with a preference for CDK9-cyclin T1. The most potent inhibitor, 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol 31b (CAN508), reduced the frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation assays. Further observed cellular effects included decreased phosphorylation of the retinoblastoma protein and the C-terminal domain of RNA polymerase II, inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53, all of which are consistent with inhibition of CDK9.
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PMID:4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. 1706 68

We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.
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PMID:Discovery of conformationally constrained tetracyclic compounds as potent hepatitis C virus NS5B RNA polymerase inhibitors. 1712 47


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