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)

Specific mutations in the human immunodeficiency virus type 1 (HIV-1) pol gene that cause zidovudine (3'-azido-2',3'-dideoxythymidine; AZT) and didanosine (2',3'-dideoxyinosine; ddI) resistance were studied. The 50% inhibitory concentrations (IC50s) of nucleosides for cloned viruses containing these mutations were compared with the IC50s of the corresponding triphosphate analogs for mutant recombinant-expressed reverse transcriptases (RTs). Changes in ddATP inhibition of RNA-dependent DNA polymerase activity fully accounted for the ddI resistance of the virus caused by a Leu-74-->Val substitution in RT, including an augmentation by the AZT-selected substitutions Thr-215-->Tyr and Lys-219-->Gln in RT. In contrast, the AZT-selected substitutions studied did not cause as great a change in the IC50 of AZT-triphosphate (AZT-TP) for polymerase as they did in the IC50 of AZT for mutant virus. In addition, the mutation at codon 74 suppressed AZT resistance in the virus caused by the mutations at codons 215 and 219 but did not suppress the AZT-TP resistance of enzyme containing these same mutations in RT. The mutation at codon 74 was found in clinical isolates whether or not the patient had received AZT prior to starting ddI therapy. AZT resistance coexisted with ddI resistance following acquisition of Leu-74-->Val in three clinical isolates, indicating that the suppressive effect of Val-74 on the AZT resistance of the virus does not occur in all genetic contexts. When this suppression of AZT resistance was seen in the virus, Val-74 did not appear to cause mutually exclusive changes in AZT-TP and ddATP binding to RT in vitro. The results of the in vitro experiments and characterization of clinical isolates suggest that there are differences in the functional effects of these AZT and ddI resistance mutations.
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PMID:pol mutations conferring zidovudine and didanosine resistance with different effects in vitro yield multiply resistant human immunodeficiency virus type 1 isolates in vivo. 768 22

The reverse transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1) is the target for many inhibitors. Amino-acid substitutions in functional regions of the enzyme that abolish reverse transcriptase activity also prevent HIV-1 replication. But selection pressure by drugs such as AZT (3'-azido-3'deoxythymidine, zidovudine), ddI (2',3'-dideoxyinosine) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) causes outgrowth of resistant variants due to non-lethal mutations in the enzyme. Reports of synergy and lack of cross-resistance between reverse transcriptase inhibitors (refs 7, 9, 10, 12-14, 17, 18, 20, 21), plus the reversal of AZT resistance by mutations induced by ddI and NNRTIs, have indicated that specific drug combinations directed at reverse transcriptase might curtail resistance. Chow et al. extended this concept in a report that specific multiple combinations of resistance mutations in the reverse transcriptase can significantly impair HIV-1 replication. They concluded that evolutionary limitations may exist to prevent the emergence of multidrug resistance to inhibitors of reverse transcriptase. We report here that HIV-1 co-resistant to AZT, ddI and the NNRTI nevirapine can be readily selected in cell culture starting with dual AZT- and ddI-resistant virus. We found no evidence for 'replication incompatible' combinations of resistance mutations, although a mutation (M184-->V) conferring oxathiolane-cytosine nucleoside resistance in reverse transcriptase completely suppressed AZT resistance in a triple-resistant background. These in vitro observations suggest that triple drug combination therapy might ultimately result in co-resistant HIV-1, although they do not preclude assessment of such combinations for treatment of HIV-1 disease.
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PMID:Convergent combination therapy can select viable multidrug-resistant HIV-1 in vitro. 769 2

Thiazolobenzimidazole (NSC 625487) was a highly potent inhibitor of human immunodeficiency virus-induced cell killing and viral replication in a variety of human cell lines, as well as fresh human peripheral blood lymphocytes and macrophages. The compound was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6. However, the agent was inactive against HIV-2 and a pyridinone-resistant strain (A17) of HIV-1, a strain which is cross-resistant to several structurally diverse members of a common pharmacologic class of nonnucleoside reverse transcriptase inhibitors. The compound selectively inhibited HIV-1 reverse transcriptase but not HIV-2 reverse transcriptase. Combinations of thiazolobenzimidazole with either AZT or ddI synergistically inhibited HIV-1 induced cell killing in vitro. Thiazolobenzimidazole also inhibited the replication of the Rauscher murine leukemia retrovirus. Thus, thiazolobenzimidazole is a new active anti-HIV-1 chemotype and may represent a subclass of nonnucleoside reverse transcriptase inhibitors with an enhanced range of anti-retroviral activity.
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PMID:Thiazolobenzimidazole: biological and biochemical anti-retroviral activity of a new nonnucleoside reverse transcriptase inhibitor. 769 15

Suksdorfin (1), which is isolated from the fruit of Lomatium suksdorfii, was found to be able to inhibit HIV-1 replication in the T cell line, H9, with an average EC50 value of 2.6 +/- 2.1 microM. In addition, suksdorfin was also suppressive during acute HIV-1 infections of peripheral blood mononuclear cells, monocyte/macrophages and the promonocytic cell line, U937. Combinations of 1 and the anti-HIV nucleosides ddI and ddC demonstrated statistical synergy in inhibiting HIV-1 replication (ddC > ddI). However, the viral inhibition mediated by combining 1 with AZT was not statistically synergistic. Furthermore, the presence of suksdorfin did not antagonize the suppression mediated by the three nucleoside reverse transcriptase inhibitors. Comparison of the structure and activity of 1 with those of ten related compounds indicated that the dihydroseselin type of pyranocoumarin possessing a 4'-isovaleryl group is important to suksdorfin's enhanced anti-HIV activity.
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PMID:Suksdorfin: an anti-HIV principle from Lomatium suksdorfii, its structure-activity correlation with related coumarins, and synergistic effects with anti-AIDS nucleosides. 777 21

One of the hallmarks of human immunodeficiency virus type 1 (HIV-1) infection is the decline in CD4+ T lymphocytes which precedes the progression from an asymptomatic state to AIDS. Apoptosis (programmed cell death) is one of the mechanisms proposed to mediate this depletion. Infectious and inactivated preparations of HIV-1LAI were compared for their potential to induce apoptosis. Analysis with fluorescence-activated cell sorting using the DNA intercalative compound propidium iodide demonstrated that apoptosis occurred only with infectious HIV-1, implying that cell surface binding and signalling by the virus alone were insufficient to trigger apoptosis. Apoptosis was further confirmed by the presence of characteristic digestion of host cell DNA and morphologically by nuclear condensation observed by transmission electron microscopy. HIV infection of CD4+ T cell lines generated an accumulation of the cells in G2/M phase of the cell cycle and cells undergoing apoptosis appeared to originate from the pool of cells in the G1 phase. Inhibitors of HIV replication were used to identify the point in the virus replicative cycle at which apoptosis is induced. The reverse transcriptase inhibitor, ddI, or the HIV protease inhibitor, RO31-8959 (Saquinavir), were added either 2 h before or 6 h after HIV inoculation. Only ddI inhibited HIV-induced apoptosis when added before inoculation; however, neither treatment was effective in preventing HIV-induced apoptosis when applied 6 h after inoculation. These data indicate that apoptosis requires a single round of reverse transcription and the expression of virion proteins, but not the maturation of progeny virions. Two agents which compete with HIV for binding to CD4+ T cells, dextran sulphate and the anti-CD4 MAb Leu3a, were effective at preventing apoptosis when added 6 h after infection, implying that a subsequent gp120-CD4 interaction at the surface of an infected cell was required to complete the apoptotic process.
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PMID:Productive infection and subsequent interaction of CD4-gp120 at the cellular membrane is required for HIV-induced apoptosis of CD4+ T cells. 789 56

Zidovudine (3'-azido-2',3'-dideoxythymidine) resistant isolates of human immunodeficiency virus type I (HIV-1) were previously demonstrated in zidovudine-treated AIDS patients. The genetic linkage of multiple mutations characteristic of zidovudine-resistance as well as dideoxyinosine-resistance were demonstrated by examining clones of viral reverse transcriptase after polymerase chain reaction (PCR) amplification of plasma culture DNA. The zidovudine-resistance mutations persisted in seven timepoints from four patients for 5 to 22 months despite cessation of zidovudine therapy (and while patients underwent ddI therapy). One patient's plasma virus isolate at 14 months possessed a genotype doubly resistant to ZDV and ddI. Virus recovered from four timepoints showed Intermediate to high levels of zidovudine-resistance. As these genotypes were mainly derived from plasma culture, the zidovudine resistant virus appears to persist and replicate well in vivo after cessation of zidovudine therapy.
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PMID:Long-term persistence of AZT-resistance mutations in the plasma HIV-1 of patients removed from AZT therapy. 815 87

The ribonucleoprotein enzyme telomerase is a specialized type of cellular reverse transcriptase which synthesizes one strand of telomeric DNA, using as the template a sequence in the RNA moiety of telomerase. We analyzed the effects of various nucleoside analogs, known to be chain-terminating inhibitors of retroviral reverse transcriptases, on Tetrahymena thermophila telomerase activity in vitro. We also analyzed the effects of such analogs on telomere length and maintenance in vivo, and on vegetative growth and mating of Tetrahymena cells. Arabinofuranyl-guanosine triphosphate (Ara-GTP) and ddGTP both efficiently inhibited telomerase activity in vitro, while azidothymidine triphosphate (AZT-TP), dideoxyinosine triphosphate (ddITP) or ddTTP were less efficient inhibitors. All of these nucleoside triphosphate analogs, however, produced analog-specific alterations of the normal banding patterns seen upon gel electrophoresis of the synthesis products of telomerase, suggesting that their chain terminating and/or competitive actions differ at different positions along the RNA template. The analogs AZT, 3'-deoxy-2',3'-didehydrothymidine (d4T) and Ara-G in nucleoside form caused consistent and rapid telomere shortening in vegetatively growing Tetrahymena. In contrast, ddG or ddI had no effect on telomere length or cell growth rates. AZT caused growth rates and viability to decrease in a fraction of cells, while Ara-G had no such effects even after several weeks in culture. Neither AZT, Ara-G, acycloguanosine (Acyclo-G), ddG nor ddI had any detectable effect on cell mating, as assayed by quantitation of the efficiency of formation of progeny from mated cells. However, AZT decreased the efficiency of programmed de novo telomere addition during macronuclear development in mating cells.
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PMID:The effects of nucleoside analogs on telomerase and telomeres in Tetrahymena. 815 19

3'-azido-3'-deoxythymidine (zidovudine-AZT) was the first clinically approved reverse transcriptase inhibitor for the treatment of acquired immunodeficiency syndrome (AIDS) and recently, 2',3'-dideoxyinosine (didanosine-ddI) has also been approved in France. These nucleoside analogs have no intrinsic anti-HIV activity and must be metabolized to their respective 5'-triphosphates by means of kinases, nucleotidases, or other activating enzymes present naturally in cells. The presence and activity of the necessary intracellular enzymes for activation of nucleoside analogs is highly dependent on species, cell type, and cell cycle stage, illustrating the importance of cellular functions in the mechanism(s) of action or toxicity of nucleoside analogs. Although the apparent plasma elimination half-life of the parent drug varies between 1 and 2 hours, the active triphosphate derivatives have intracellular half-lives between 4 and 12 h with 2',3'-dideoxyadenosine-5'-triphosphate (ddATP), the active component of ddl being one of the most stable with an intracellular half-life of 8 to 12 hours which result in relatively infrequent dosing as compared to other classes of potential anti-HIV drugs under development. The multifactorial mechanism(s) of toxicity of this class of drugs likely explains the different spectrums of toxicity observed with the various nucleoside analogs, and demonstrates the uniqueness of each compound. Recently, AZT-resistant strains have been isolated from AZT-treated patients, probably reflecting a sequential acquisition of amino-acid mutations in the HIV-RT. Of importance, cross-resistance was demonstrated with other compounds with an 3'-azido group, but no cross-resistance was detected with either ddl of 2',3'-dideoxycytidine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[What is known about the cellular and molecular pharmacodynamics of nucleosides?]. 830 21

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

Nucleotide heterodimers were synthesized and examined for their inhibitory effects on the replication of human immunodeficiency virus type 1 (HIV-1), including HIV-1 reverse transcriptase (RT) inhibitor-resistant mutants. 3'-Azido-3'-deoxythymidilyl-(5')-phospho-(5')-6-[(3', 5'-dimethylphenyl)thio]-5-ethyl-1-[(2-hydroxyethoxy)methyl]uracil (AZT-P-E-HEPU-dM) and 3'-azido-3'-deoxythymidilyl-(5')-phospho-(5')-2', 3'-dideoxyinosine (AZT-P-ddI) proved to be highly potent and selective inhibitors of HIV-1 (IIIB strain) in MT-4 cells. The mechanism of inhibition by these heterodimers may be attributed to their degradation and the formation of each constituent. AZT-P-E-HEPU-dM was also markedly inhibitory to an AZT-resistant mutant (HIV-1-IIIB/AZT) and an E-HEPU-dM-resistant mutant (HIV-1-IIIB-R). However, AZT-P-ddI was found to have a less inhibitory effect on HIV-1-IIIB/AZT than on HIV-1-IIIB. The heterodimers of (5',5') AZT and ribavirin (AZT-P-Ribavirin) and (5',5') ddI and ribavirin (ddI-P-Ribavirin) were also synthesized: AZT-P-Ribavirin inhibited HIV-1 replication, but ddI-P-Ribarvirin did not.
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PMID:Antiviral activities of nucleotide heterodimers against human immunodeficiency virus type 1 in vitro. 879 15


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