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)

Several cell clones possessing the human immunodeficiency virus type 1 (HIV-1) genome, consisting of an almost full-length DNA sequence, were isolated by limiting dilution of the clonal cell line M10 derived from MT-4 that survived infection with HIV-1 vpr mutant (M10/vpr-). One of the isolated clones (termed Vpr-1) expressed only doubly spliced mRNA, but not unspliced or singly spliced mRNA. Western blots of Vpr-1 revealed the presence of the nef translation product, although no expression of major structural genes such as gag, pol, and env was detected by indirect immunofluorescence and assay of reverse transcriptase activity. These HIV-1 phenotypes differed greatly from those of the original M10/vpr-, most of which expressed major structural HIV-1 proteins. Despite undetectable levels of env expression in Vpr-1, CD4 antigens were greatly down-modulated on the surface without alteration of steady-state levels of CD4 mRNA expression, similar to M10/vpr-. These HIV-1 phenotypes in Vpr-1 did not change after the treatment of the cells with both phorbol 12-myristate 13-acetate and phytohemagglutinin. Therefore, the abnormal HIV-1 life cycle in Vpr-1 seems to be due to some viral factor(s), as well as cellular factors. Thus, Vpr-1 could be a useful model for understanding one HIV-1 latent form.
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PMID:Persistently human immunodeficiency virus type 1-infected T cell clone expressing only doubly spliced mRNA exhibits reduced cell surface CD4 expression. 846 32

Halogenated gomisin J (a derivative of lignan compound), represented by the bromine derivative 1506 [(6R, 7S, S-biar)-4,9-dibromo-3,10-dihydroxy-1,2,11,12-tetramethoxy-6, 7-dimethyl-5,6,7,8- tetrahydrodibenzo[a,c]cyclo-octene], was found to be a potent inhibitor of the cytopathic effects of human immunodeficiency virus type 1 (HIV-1) on MT-4 human T cells (50% effective dose, 0.1 to 0.5 microM). Gomisin J derivatives were active in preventing p24 production from acutely HIV-1-infected H9 cells. The selective indices (toxic dose/effective dose) of these compounds were as high as > 300 in some systems. 1506 was active against 3'-azido-3'-deoxythymidine-resistant HIV-1 and acted synergistically with AZT and 2',3'-ddC. 1506 inhibited HIV-1 reverse transcriptase (RT) in vitro but not HIV-1 protease. From the time-of-addition experiment, 1506 was found to inhibit the early phase of the HIV life cycle. A 1506-resistant HIV mutant was selected and shown to possess a mutation within the RT-coding region (at position 188 [Tyr to Leu]). The mutant RT expressed in Escherichia coli was resistant to 1506 in the in vitro RT assay. Some of the HIV strains resistant to other nonnucleoside HIV-1 RT inhibitors were also resistant to 1506. Comparison of various gomisin J derivatives with gomisin J showed that iodine, bromine, and chlorine in the fourth and ninth positions increased RT inhibitory activity as well as cytoprotective activity.
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PMID:Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1 reverse transcriptase. 854 Jul 6

The organization of the metallothionein (MT) gene family has been demonstrated to be much more complex in humans than in the mouse, and possibly rodents in general. For humans, the MTs are encoded by a family of genes located at 16q13 representing 10 functional and 7 non-functional MT isoforms. In the present study, the 5' and 3' untranslated region sequences of the highly conserved, functional MT genes were utilized to generate primer pairs for the analysis of isoform-specific MT mRNA using reverse transcriptase-polymerase chain reaction (RT-PCR). Human kidneys from 13 weeks gestation through adulthood were examined for the expression of MT protein and mRNA. Immunohistochemical analysis demonstrated MT immunoreactivity to be confined exclusively to the proximal tubules of the adult and developing kidney. For all MT-positive cells, MT was localized in the cytoplasm and nuclear localization was variable. There was no correlation between nuclear staining and stage of development. Of the 10 MT genes examined (MT-1A, MT-1B, MT-1E, MT-1F, MT-1G, MT-1H, MT-1X, MT-2A, MT-3, and MT-4), mRNAs representing the MT-1E, MT-1F, MT-1X, and MT-2A genes were consistently expressed in all samples regardless of gestational age. There was no indication of a 'fetal form' of MT analogous to that noted to occur in human liver. Messenger RNA for the MT-1A gene was detected in 2 of 6 renal samples without correlation to gestational age. In no instance was mRNA for the MT-1B, MT-1G, MT-1H, MT-3 or MT-4 genes detected. These studies detail the initial determination of MT gene expression in the human renal system and provide the PCR primers for testing and determination of MT gene expression in other organ systems.
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PMID:Isoform-specific expression of metallothionein mRNA in the developing and adult human kidney. 861 55

4-(2,6-Dichlorophenyl)-1,2,5-thiadiazol-3-yl N,N-dialkylcarbamate (TDA) derivatives were found to be highly potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in a variety of cell cultures. The most potent congener of TDA derivatives, RD4-2024, inhibited HIV-1 replication by 50% at concentrations of 12.5 and 4.8 nM in MT-4 cells and peripheral blood mononuclear cells, respectively. These concentrations were more than 2,000- and 30,000-fold lower than its 50% cytotoxic concentrations, respectively. Although the TDA derivatives were active against 3'-azido-3'-deoxythymidine-resistant HIV-1, no antiviral activities were observed against HIV-2 and nonnucleoside reverse transcriptase inhibitor-resistant mutants of HIV-1. The TDA derivatives inhibited recombinant HIV-1 reverse transcriptase activity, depending on the template-primer used for the assay. However, they did not interact with HIV-2 reverse transcriptase. Thus, the TDA derivatives belong to the family of nonnucleoside reverse transcriptase inhibitors. Because of their potent anti-HIV-1 activities in vitro and their low levels of toxicity in mice, the TDA derivatives deserve further evaluation as candidate drugs for the treatment of patients with AIDS.
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PMID:Potent and specific inhibition of human immunodeficiency virus type 1 replication by 4-(2,6-dichlorophenyl)-1,2,5-thiadiazol-3-Y1 N,N-dialkylcarbamate derivatives. 861 92

A series of omega-undecanoic amides of lup-20(29)-en-28-oic acid derivatives were synthesized and evaluated for activity in CEM 4 and MT-4 cell cultures against human immunodeficiency virus type 1 (HIV-1) strain IIIB/LAI. The potent HIV inhibitors which emerged, compounds 5a, 16a, and 17b, were all derivatives of betulinic acid (3beta-hydroxylup-20(29)-en-28-oic acid). No activity was found against HIV-2 strain ROD. Compound 5a showed no inhibition of HIV-1 reverse transcriptase activity with poly(C).oligo(dG) as template/primer, nor did it inhibit HIV-1 protease. Additional mechanistic studies revealed that this class of compounds interfere with HIV-1 entry in the cells at a postbinding step.
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PMID:Betulinic acid derivatives: a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action. 867 41

A novel series of omega-aminoalkanoic acid derivatives of betulinic acid were synthesized and evaluated for their activity against human immunodeficiency virus (HIV). The anti-HIV-1 activity of several members of this new series was found to be in the nanomolar range in CEM 4 and MT-4 cell cultures. The optimization of the omega-aminoalkanoic acid side chain is described. The presence of an amide function within the side chain was found important for optimal activity. RPR 103611 (14g), a statine derivative, was found to be inactive against HIV-1 protease, reverse transcriptase, and integrase as well as on gp120/CD4 binding. "Time of addition" experiments suggested interaction with an early step of HIV-1 replication. As syncytium formation, but not virus-cell binding, seems to be affected, betulinic acid derivatives are assumed to interact with the postbinding virus-cell fusion process.
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PMID:Betulinic acid derivatives: a new class of specific inhibitors of human immunodeficiency virus type 1 entry. 867 42

The covalent attachment of a phospholipid moiety, bound to the 5'-ends of phosphodiester and phosphorothioate oligonucleotides (L-ODNs and LS-ODNs), was achieved using H-phosphonate chemistry, and the lipid-oligonucleotides were assayed for the inhibition of virus replication in HIV-1 infected MT-4 cells. In the anti-HIV activity test, lipid-phosphorothioate oligonucleotides showed higher anti-HIV activities than non-lipid-phosphorothioate oligonucleotides, at the low concentration of 0.04 microM. LS-ODNs can inhibit HIV-1 reverse transcriptase activity through interactions with the enzyme. We found that the covalent attachment of a phospholipid group to the 5'-end of the phosphorothioate oligonucleotide enhances its nonsequence specific anti-HIV activity.
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PMID:5'-linked lipid-oligodeoxyridonucleotide derivatives as inhibitors of human immunodeficiency virus replication. 873 48

Bicyclams have recently been identified as potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) replication. The prototype of this series, JM3100 exhibits anti-HIV potency at concentrations ranging from 0.001 to 0.01 micrograms/ml. JM3100 proved to be active when tested against HIV strains resistant to the reverse transcriptase (RT) inhibitors 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (DDI), 3TC, alpha APA and TIBO, at roughly the same concentrations as for the wild-type strain. The virus was passaged in vitro in the presence of increasing concentrations of either TIBO or alpha APA alone or in combination with JM3100. The combination between TIBO, or alpha APA, and JM3100 delayed the development of TIBO- and alpha APA-resistant strains, without emergence of resistance to JM3100. In separate experiments, it took more than 60 passages (300 days) in MT-4 cells and 20 passages (140 days) in peripheral blood lymphocyte (PBL) cells for the virus to become resistant to JM3100. The JM3100-resistant virus showed cross-resistance to sulfated polysaccharides such as dextran sulfate (DS), pentosan sulfate (PS), heparin and cyclodextrin sulfate (CDS), suggesting that these compounds may share a common mechanism of action. Furthermore, the inhibitory effect of JM3100 on virus-induced syncytium formation was enhanced in the presence of heparin. The results presented here provide further support for the bicyclams as attractive candidate drugs for the chemotherapy of HIV infections.
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PMID:Antiviral activity of the bicyclam derivative JM3100 against drug-resistant strains of human immunodeficiency virus type 1. 873 8

Several novel alkenyldiarylmethane (ADAM) non-nucleoside HIV-1 reverse transcriptase inhibitors were synthesized. The most potent of these proved to be 3',3"-dibromo-4',4"-dimethoxy-5'5"-bis(methoxycarbonyl)-1,1-diphenyl-1-+ ++heptene (8) ADAM 8 inhibited the cytopathic effect of HIV-1 in CEM cell culture with an EC50 value of 7.1 microM and was active against an array of laboratory strains of HIV-1 in CEM-SS and MT-4 cells, but was inactive as an inhibitor of HIV-2. In common with the other known non-nucleoside reverse transcriptase inhibitors, ADAM 8 was an effective inhibitor of HIV-1 reverse transcriptase (IC50 1 microM) with poly(rC).oligo(dG), but not with poly(rA).oligo(dT), as the template/primer. ADAM 8 was inactive against HIV-1 reverse transcriptases containing non-nucleoside reverse transcriptase inhibitor resistance mutations at residues 101, 106, 108, 139, 181, 188, and 236, while it remained active against enzymes with mutations at residues 74, 98, 100, 103, and at 103/181. An AZT-resistant virus having four mutations in reverse transcriptase was more sensitive to inhibition by ADAM 8 than the wild-type HIV-1. In addition, ADAM 8 displayed synergistic activity with AZT, but lacked synergy with ddI. ADAM 8 or a structurally related analog may therefore be useful as an antiviral agent in combination with AZT or with other NNRTIs that are made ineffective by mutations at residues which do not confer resistance to ADAM 8.
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PMID:Synthesis and biological evaluation of certain alkenyldiarylmethanes as anti-HIV-1 agents which act as non-nucleoside reverse transcriptase inhibitors. 875 44

We have investigated viral breakthrough during a long-term culture of HIV-1-infected cells with the non-nucleoside reverse transcriptase inhibitors (NNRTIs) 6-benzyl-1-ethoxymethyl-5-isopropyluracil (MKC-442), nevirapine and loviride (alpha-APA). When the compounds were examined for their inhibitory effects on HIV-1 (HE strain) replication in MT-4 cells on day 4 after virus infection, the 50% effective concentrations (EC50) of MKC-442, nevirapine and loviride were 9.4, 98 and 21 nM, respectively. After a 48-day culture period, MKC-442, nevirapine and loviride completely inhibited viral breakthrough at concentrations of 1, 5 and 1 microM, respectively. These concentrations were 50-100-fold higher than their EC50 values. When the cells were treated with either MKC-442 (0.04 and 0.2 microM), nevirapine (0.2 and 1 microM) or loviride (0.04 and 0.2 microM) in combination with AZT (0.005 microM), only the combination of 0.2 microM MKC-442 with 0.005 microM AZT could completely inhibit the breakthrough of HIV-1 after a 68-day culture period. Polymerase chain reaction (PCR) analysis revealed that no proviral DNA was detected in the cells treated with this combination. Except for two combinations (0.04 microM MKC-442 + 0.005 microM AZT and 0.04 microM loviride + 0.005 microM AZT), all of the viruses isolated during combination treatments had various amino acid mutations in their reverse transcriptase (RT). These results indicate that the combination treatment with a relatively high dose of MKC-442 and a low dose of AZT may have potential to suppress the emergence of drug resistance during a long-term treatment in vivo and should be further pursued in HIV-1-infected patients.
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PMID:Complete inhibition of viral breakthrough by combination of MKC-442 with AZT during a long-term culture of HIV-1 infected cells. 879 10


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