Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The emergence of HIV/AIDS as a disease spread through sexual intercourse has prompted the search for safe and effective vaginal and rectal microbicides for curbing mucosal viral transmission via semen. Since endogenous reverse transcription is implicated in augmenting the sexual transmission of HIV-1 infection, potential microbicides should have the inherent ability to optimally inhibit both wild-type and drug-escape mutants. The non-nucleoside reverse transcriptase inhibitors (NNRTIs), which bind to an allosteric site on RT, are an important arsenal of drugs against HIV-1. The clinical success of NNRTI-based HIV/AIDS therapies has led to extensive structural and molecular modelling studies of enzyme complexes and chemical synthesis of second- and third-generation NNRTIs. Rationally designed NNRTIs deduced from changes in binding pocket size, shape and residue character that result from clinically observed NNRTI resistance-associated mutations exhibit high binding affinity for HIV-1 RT and robust anti-HIV activity against the wild-type and drug-escape mutants without cytotoxicity. Notably, membrane permeable tight binding NNRTIs have the ability to inactivate cell-free as well as cell-associated HIV-1 in semen without metabolic activation. Consequently, NNRTIs currently under development as experimental microbicides include thiourea-PETT (where PETT stands for phenethylthiazolylthiourea) derivatives (PHI-236, PHI-346 and PHI-443), urea-PETT derivatives (MIV-150), oxypyrimidines (S-DABOs), thiocarboxanilides (UC-781) and diarylpyrimidines (TMC-120). Mucoadhesive formulations of these NNRTIs have been studied for safety and efficacy in animal models and some have entered Phase I safety testing in humans. This review focuses on the structural, biological and preclinical studies relevant to the clinical development of these NNRTIs as molecular virucides intended to prevent the sexual transmission of HIV-1.
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PMID:Dawn of non-nucleoside inhibitor-based anti-HIV microbicides. 1643 62

In an attempt to discover anti-HIV agents with much reduced cytotoxicity from the currently available HIV-reverse transcriptase inhibitors, AZT conjugates of cholanic acids, 2-imidazolidone-4-carboxylic acid and its derivatives, and N,N'-disubstituted 5-hydroxy-tetrahydropyrimidin-2-ones have been synthesized and their anti-HIV profiles determined with CEM-SS cell line. The AZT conjugates with 2-imidazolidone-4-carboxylic acid and 2-pyrrolidone-5-carboxylic acid through an ester linkage, and with N,N'-diphenyl-5-hydroxy-tetrahydropyrimidin-2-one through a succinate tether showed significantly higher therapeutic indexes than AZT while they also retained or enhanced AZT's anti-HIV activity. Thus, structural features that favor the desired therapeutic profile of the conjugates appear to include a five-membered ring cyclic urea or lactam, and six-membered ring cyclic urea with N,N'-diphenyl substitution.
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PMID:New AZT conjugates as potent anti-HIV agents. 1644 Sep 84

Two adsorption-elution concentration methods, both involving negatively charged membranes, were evaluated in order to monitor hepatitis A virus (HAV) contamination in tap, river, mineral and coastal water samples: elution with urea-arginine phosphate buffer/reconcentration with magnesium chloride (method 1); and sodium hydroxide elution/reconcentration with a commercial concentrator (method 2). Nested (qualitative) reverse transcriptase PCR (RT-PCR) and real-time (quantitative) RT-PCR were used to detect and quantify HAV RNA in concentrated water samples. For concentrating HAV, method 1 was found to be the most suitable for tap water and method 2 most suitable for mineral water. HAV inoculated experimentally was detected in river water samples by both methods and in coastal water samples by neither method. The detection limits were 6 x 10(9) g equiv./ml for qualitative PCR and 60 g equiv./ml for quantitative PCR. In a field application study, HAV was detected in 20% of river and tap water samples but not in coastal or mineral water samples. River water samples contained subgenotype IA, and tap water samples contained subgenotype IB. It is concluded that, although influencing qualitative PCR, the concentration method does not affect quantitative PCR, which could therefore be used for all types of water samples. Both techniques are recommended for detecting HAV in environmental water samples.
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PMID:Evaluation of methods used to concentrate and detect hepatitis A virus in water samples. 1688

Novel compounds, which can be considered as conformationally restricted analogues of MKC-442, have been synthesized and tested as inhibitors of the reverse transcriptase of human immunodeficiency virus type-1 (HIV-1). Reaction of urea with a beta-ketoester furnished 6,7,8,9-tetrahydro-9-phenyl-1H-cyclohepta[d]pyrimidine-2,4-(3H,5H)-dione (6a) and 6,7,8,9-tetrahydro-9-p-tolyl-1H-cyclohepta[d]pyrimidine-2,4-(3H,5H)-dione (6b) which were then alkylated at the N-1 position with chloromethyl ether, allyl bromide and benzyl bromide to afford the target compounds 7a-b, 8a-b, 9 and 10, respectively. The seven-membered, annelated compounds have a relatively rigid structures and can lock the orientation of the aromatic ring. Chemical modification at N-1 of the pyrinidine ring and the 9-phenyl ring was attempted, with the aim of improving the antiretroviral activity. In particular, replacement of the aliphatic group with the phenyl moiety at the terminus of N-1 side chain can enhance the activity. The most active compounds showed activity in the low micromolar range with IC50 values comparable to that of nevirapine. The biological activity results are in accordance with the docking results.
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PMID:The design and synthesis of 9-phenylcyclohepta[d]pyrimidine-2,4-dione derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase. 1703 13

Extrahepatic bioartificial liver devices should provide an intact urea cycle to detoxify ammonia. The C3A cell line, a subclone of the hepatoma-derived HepG2 cell line, is currently used in this context as it produces urea, and this has been assumed to be reflective of ammonia detoxification via a functional urea cycle. However, based on our previous findings of perturbed urea-cycle function in the non-urea producing HepG2 cell line, we hypothesized that the urea produced by C3A cells was via a urea cycle-independent mechanism, namely, due to arginase II activity, and therefore would not detoxify ammonia. Urea was quantified using (15)N-ammonium chloride metabolic labelling with gas chromatography-mass spectrometry. Gene expression was determined by real-time reverse transcriptase-PCR, protein expression by western blotting, and functional activities with radiolabelling enzyme assays. Arginase inhibition studies used N(omega)-hydroxy-nor-L-arginine. Urea was detected in C3A conditioned medium; however, (15)N-ammonium chloride-labelling indicated that (15)N-ammonia was not incorporated into (15)N-labelled urea. Further, gene expression of two urea cycle genes, ornithine transcarbamylase and arginase I, were completely absent. In contrast, arginase II mRNA and protein was expressed at high levels in C3A cells and was inhibited by N(omega)-hydroxy-nor-L-arginine, which prevented urea production, thereby indicating a urea cycle-independent pathway. The urea cycle is non-functional in C3A cells, and their urea production is solely due to the presence of arginase II, which therefore cannot provide ammonia detoxification in a bioartificial liver system. This emphasizes the continued requirement for developing a component capable of a full repertoire of liver function.
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PMID:Cells for bioartificial liver devices: the human hepatoma-derived cell line C3A produces urea but does not detoxify ammonia. 1768 Jun 61

The transcription factor peroxisome proliferator-activated receptor (PPAR) alpha plays an important role in lipid homeostasis. In this study, we examined whether the down-regulation of PPAR-alpha gene expression is associated with dyslipidemia in a rat model of chronic renal failure (CRF). Rats with laboratory-induced uremia by 5/6 nephrectomy were bled at 2 weeks and 10 weeks after the nephrectomy to produce conditions. For the sake of convenience, the rats observed at postoperative week 2 were defined as acute renal failure (ARF) and those observed at week 10 were defined as CRF. Lipids in lipoprotein fractions were measured by high-performance liquid chromatography. The abundance of PPAR-alpha messenger RNA (mRNA) in the liver was measured by reverse transcriptase-polymerase chain reaction. Serum creatinine and blood urea nitrogen levels rose with the progression of renal failure, but the total protein levels remained constant. Serum triglyceride in ARF rats remained unchanged from the level in sham-operated control rats, whereas that in CRF rats was 66% higher than the control level. Serum cholesterol was elevated 1.5-fold in ARF rats and 2-fold in CRF rats compared with the sham-operated counterparts. As with triglyceride, very low-density lipoprotein remained unchanged in ARF rats but rose substantially in CRF rats. All of the major lipoprotein fractions were elevated in CRF rats. These lipid and lipoprotein changes were significantly associated with creatinine and blood urea nitrogen levels. The PPAR-alpha mRNA expression in the liver was unchanged in ARF rats but was 44% lower in CRF rats. The PPAR-alpha mRNA expression was inversely correlated with serum creatinine and lipids in the overall rats. Our results indicate that PPAR-alpha mRNA expression is down-regulated in the liver of CRF rats and that this down-regulation may play a crucial role in the development of dyslipidemia.
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PMID:Decreased peroxisome proliferator-activated receptor alpha gene expression is associated with dyslipidemia in a rat model of chronic renal failure. 1799 26

Increased risk of cardiovascular disease in end-stage renal disease (ESRD) has been explained by accelerated atherosclerosis and impaired angiogenesis, in which endothelial progenitor cells (EPC) may play key roles. Circulating cells with endothelial progenitor phenotype have not been evaluated in children with ESRD. Using a quantitative reverse transcriptase polymerase chain reaction (RT-PCR) approach, we measured endothelial-specific and progenitor-associated genes VE-cadherin (VE-C), CD146, CD31, tyrosine-protein kinase receptor (Tie-2), Flk1, CD133, and growth factors promoting EPC function, vascular endothelial growth factor (VEGF), erythropoietin (EPO), and stromal cell-derived factor-1 (SDF-1) in the blood of pediatric patients undergoing hemodialysis and after transplantation. Patients' metabolic parameters were correlated with EPC marker gene levels. Compared with controls, circulating VE-cadherin, CD146, Flk1, VEGF, and EPO RNA levels were decreased in ESRD and normalized in transplanted patients. Levels of VE-cadherin, which were the most significantly reduced in ESRD (p = 0.001) inversely correlated in all of the patient population with serum urea and creatinine concentration, whereas among the ESRD group showed an inverse correlation with diastolic blood pressure (BP), interventricular septum thickness (IVST), and left ventricular mass index. Pediatric ESRD patients may have lower angiogenic potential and increased cardiovascular morbidity, because of decreased expression of circulating endothelial cell specific transcripts. Prospective studies are required to link this expression pattern and its restoration in transplanted patients to cardiovascular outcome.
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PMID:Molecular evaluation of circulating endothelial progenitor cells in children undergoing hemodialysis and after kidney transplantation. 1885 88

The monoamine, 5-hydroxytryptamine (5-HT), stimulates contraction of human uterine smooth muscle (myometrium), but the receptor subtypes involved have not been characterized. We studied the effects of a range of 5-HT receptor subtype-selective agonists and antagonists in isolated strips of myometrium obtained at the time of caesarean section. The 5-HT(1A) receptor agonist, 8-hydroxy-2-dipropylaminotetralin, produced an increase in contractions that was highly variable, of low potency, and was not significantly inhibited by the 5-HT(1A) antagonist WAY100635 [[O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide]. The 5-HT(2) receptor agonist, alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT), produced a strong, consistent, and concentration-dependent stimulation of contractions (pEC(50) = 7.60 +/- 0.10, n = 5). The 5-HT(2A) receptor antagonist, ketanserin [3-[2-[4-(4-fluoro benzoyl)-piperidin-1-yl]ethyl]-1H-quinazoline-2,4-dione], caused a parallel shift in the response to alpha-Me-5-HT, with a pK(B) value consistent with its known affinity for the 5-HT(2A) receptor (pK(B) = 8.47 +/- 0.16, n = 5), but it had no effect on the response to oxytocin. The 5-HT(2B) and 5-HT(2C) receptor agonists, BW723C86 [(alpha-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine)] and Ro-60-01-75 [(S)-2-(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine fumarate], produced inconsistent responses at potencies that were lower than expected for activation of their cognate receptors. The response to alpha-Me-5-HT was unaffected by the 5-HT(2B) and 5-HT(2C) receptor antagonists, SB204741 [(N-(1-methyl-1H-indolyl-5-yl)-N-(3-methyl-5-isothiazolyl)urea)] and RS102221 [8-[5-(2,4-dimethoxy-5-(4-trifluoromethyl phenylsulphonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione]. The 5-HT(1B/1D) receptor agonist, sumatriptan [1-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-N-methyl-methanesulfonamide], the 5-HT(4) agonist, cisapride [4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidyl]-2-methoxy-benzamide], and the 5-HT(7) agonist, AS19 [(2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin], all had no effect on myometrial contractility. 5-HT(2A) receptor mRNA and immunoreactivity were identified using reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry. Specific binding of [(3)H]ketanserin was demonstrated. This study provides strong evidence for the expression of contractile 5-HT(2A) receptors in pregnant human myometrium, and this receptor is a potential target for novel uterotonic therapies.
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PMID:Characterization of serotonin receptors in pregnant human myometrium. 1907 42

A 60 kDa antifungal amidase was purified from Peltophorum pterocarpum [corrected] seeds using an isolation procedure that entailed ion-exchange chromatography on Q-Sepharose, ion-exchange chromatography on DEAE-cellulose and FPLC-gel filtration on Superdex 75. Unlike most other antifungal proteins isolated previously, it was adsorbed on Q-Sepharose and DEAE-cellulose. The isolated protein, designated as peltopterin, exhibited an N-terminal amino acid sequence closely resembling those of amidases. It exhibited amidase activity and digested iodoacetamide with an optimum pH and temperature at pH 9 and 50 degrees C, respectively. It also hydrolyzed acrylamide and urea. It impeded mycelial growth in Rhizotonia solani with an IC(50) of 0.65 microm. Chitin deposition at hyphal tips in R. solani was observed by staining with Congo red after incubation with peltopterin. Its antifungal activity was stable throughout pH 0-14 and 25-100 degrees C. It potently inhibited HIV-1 reverse transcriptase with an IC(50) of 27 nm.
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PMID:First report of an antifungal amidase from Peltophorum pterocarpum. [corrected]. 1968 18

This study examined the question of whether deficiency of xCT, a cystine-transporter gene, exacerbates ischemia-reperfusion-induced acute renal failure (ARF). Two weeks after the right nephrectomy of male mice at 16-18weeks of age, the left renal vessels were clamped for 45min to induce renal ischemia. After (24h) induction of ischemia, xCT(-/-) mice had elevated concentrations of blood urea nitrogen and creatinine indicative of ARF, while in xCT(+/-) and xCT(+/+) mice, these parameters did not differ from the sham-operated mice. Immunohistochemical analyses of kidneys using antibodies against the oxidative stress markers revealed stronger staining in xCT(-/-) mice compared with xCT(+/+) mice. Induction of xCT mRNA in the kidneys of xCT(+/+) mice was demonstrated using reverse transcriptase (RT)-PCR analysis and was further confirmed using quantitative RT-PCR. These data provide the first in vivo evidence that xCT is induced by oxidative stress and helps prevent ischemia-reperfusion injury to kidneys.
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PMID:Aggravation of ischemia-reperfusion-triggered acute renal failure in xCT-deficient mice. 1969 16


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