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

---

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

In an attempt to combine the HIV-inhibitory capacity of 2',3'-dideoxynucleoside (ddN) analogues and non-nucleoside reverse transcriptase (RT) inhibitors (NNRTI), we have designed, synthesized, and evaluated for their anti-HIV activity several dimers of the general formula [ddN]-(CH2)n-[NNRTI]. These dimers combine in their structure a ddN such as AZT and a NNRTI such as TSAO-T and HEPT linked through an appropriate spacer between the N-3 of the thymine base of both compounds. The [TSAO-T]-(CH2)n-[AZT] dimers proved markedly inhibitory to HIV-1. Also, if AZT was replaced by thymidine in the dimer molecules, potent anti-HIV-1 activity was observed. However, although the compounds proved inhibitory to HIV-1, they were less potent inhibitors than the parent compounds from which they were derived. None of the dimers were endowed with anti-HIV-2 activity. In contrast with the TSAO-T monomers, none of the TSAO-T-containing dimers proved markedly cytotoxic to the cells. There was a clear trend toward decreased antiviral potency with lengthening the methylene spacer in the [TSAO-T]-(CH2)n-[AZT] dimers.
...
PMID:Synthesis and anti-HIV activity of [AZT]-[TSAO-T] and [AZT]-[HEPT] dimers as potential multifunctional inhibitors of HIV-1 reverse transcriptase. 753 89

A series of benzophenone derivatives has been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (RT) and the growth of HIV-1 in MT-4 cells. Through the use of the structure-activity relationships within this series of compounds and computational chemistry techniques, a binding conformation is proposed. The SAR also indicated that the major interactions of 1h with the RT enzyme are through hydrogen bonding of the amide and benzophenone carbonyls and pi-orbital interactions with the benzophenone nucleus and an aromatic function separated from the benzophenone by a suitable spacer group. The crystal structure of compound 1h has been determined. A number of compounds with potent inhibitory activity against HIV-1 RT and HIV in cellular assays at levels comparable with AZT and our efforts to identify a metabolically stable analogue are described.
...
PMID:Benzophenone derivatives: a novel series of potent and selective inhibitors of human immunodeficiency virus type 1 reverse transcriptase. 753 90

To develop an animal model for the therapy of AIDS with human immunodeficiency virus type 1 (HIV-1)-specific reverse transcriptase (RT) inhibitors, we recently constructed a hybrid simian immunodeficiency virus (SIV)/HIV-1 in which the RT gene of SIV was replaced by the RT gene of HIV-1. This chimaeric virus, designated RT-SHIV, was found to be markedly sensitive to the inhibitory effects of both nucleoside (ddN) and non-nucleoside RT inhibitors (NNRTIs). In contrast, SIV was inhibited only by ddNs (i.e., 3TC and AZT), but not NNRTIs. When RT-SHIV was grown in the presence of 3TC, nevirapine, TSAO-m3T or the thiocarboxanilide UC-42 drug-resistant mutant virus strains emerged in cell culture as rapid as for HIV-1(IIIB). The antiviral sensitivity/resistance spectrum of the mutant RT-SHIV strains against NNRTIs and ddNs, and the nature of the mutations that appeared in their RT were similar to those of the mutant HIV-1 strains that were selected under identical experimental conditions. Infection of macaques with RT-SHIV may be a useful tool for studying the mechanism of NNRTI-resistance development and the therapy of NNRTI-resistant viruses in an animal model.
...
PMID:Sensitivity/resistance profile of a simian immunodeficiency virus containing the reverse transcriptase gene of human immunodeficiency virus type 1 (HIV-1) toward the HIV-1-specific non-nucleoside reverse transcriptase inhibitors. 754 Dec

MKC-442, a derivative of the non-nucleoside reverse transcriptase (RT) inhibitor 1-[(2-hydroxyethoxy)methyl)-6-(phenylthio)thymidine (HEPT), showed potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) replication in vitro, using a range of host-cell/virus systems including human peripheral blood mononuclear cells infected with primary clinical isolates. MKC-442 was evaluated in combination with the nucleoside analogues AZT, ddI and ddC, the non-nucleoside RT inhibitor nevirapine, the HIV-1 proteinase inhibitor Ro-31-8959, and the alpha-glucosidase 1 inhibitor, MDL-28,574, using a cell viability assay. Drug interactions were evaluated by the isobologram technique and by calculating combination indices. Notable synergistic inhibition of HIV-1 replication was observed when MKC-442 was combined with AZT and MDL-28,574 and moderate synergy with ddI. In combination with ddC, nevirapine or Ro-31-8959, only a slightly better than additive effect was observed. Impressive synergy was seen using the three-drug combinations of MKC-442, AZT and MDL-28,574 or MKC-442, AZT and Ro-31-8959. No additional cytotoxicity was observed as measured by [3H]thymidine incorporation by concanavalin A-stimulated peripheral blood mononuclear cells, when MKC-442 was combined with any of the above-mentioned compounds. The use of MKC-442 in a two- or three-drug combination regimen with other RT inhibitors, a proteinase inhibitor or an alpha-glucosidase 1 inhibitor should be considered for HIV-1-related chemotherapy.
...
PMID:The inhibition of human immunodeficiency virus type 1 in vitro by a non-nucleoside reverse transcriptase inhibitor MKC-442, alone and in combination with other anti-HIV compounds. 754 19

Nitric oxide (NO) which is produced by activation of Ca2+/calmodulin-dependent NO synthase is known to induce neuronal damage. We examined the effects of 3'-azido-2',3'-dideoxythymidine (AZT, a reverse transcriptase inhibitor), pentamidine (a therapeutic drug for Pneumocystis carinii pneumonia) and calmodulin antagonists such as trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) on NO synthase activation. Although AZT had no effect on the activity of constitutive neuronal NO synthase, pentamidine inhibited the activation of neuronal NO synthase as did trifluoperazine and W-7. The inhibition by pentamidine was prevented by the addition of purified calmodulin. In addition, pentamidine inhibited calmodulin-dependent activation of neuronal NO synthase purified from rat cerebellum. From these results, it is suggested that pentamidine inhibits the neuronal NO synthase activation by probably acting as a calmodulin antagonist.
...
PMID:Inhibition of constitutive nitric oxide synthase in the brain by pentamidine, a calmodulin antagonist. 754 7

Combinations of antiretroviral drugs that prevent or delay the appearance of drug-resistant human immunodeficiency virus-type 1 (HIV-1) mutants are urgently required. Mutants resistant to 3'-azidothymidine (AZT, zidovudine) became phenotypically sensitive in vitro by mutation of residue 184 of viral reverse transcriptase to valine, which also induced resistance to (-)2'-deoxy-3'-thiacytidine (3TC). Furthermore, AZT-3TC coresistance was not observed during extensive in vitro selection with both drugs. In vivo AZT-3TC combination therapy resulted in a markedly greater decreased in serum HIV-1 RNA concentrations than treatment with AZT alone, even though valine-184 mutants rapidly emerged. Most samples assessed from the combination group remained AZT sensitive at 24 weeks of therapy, consistent with in vitro mutation studies.
...
PMID:Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. 754 4

Azidothymidine (zidovudine, AZT) used for treatment of HIV infection blocks the viral reverse transcriptase after phosphorylation by cellular enzymes. The first step in this reaction is the formation of AZT monophosphate, primarily catalyzed by host cytoplasmatic thymidine kinase (TK1). The activity of TK1 was determined in extracts of PHA-stimulated peripheral blood mononuclear cells (PBMCs) from 20 healthy volunteers and 49 HIV-infected patients at different stages of disease. In both groups we found a large intra- and interindividual variation of TK activity. Because TK1 expression is cell cycle regulated the proportion of stimulated cells was determined in the samples and the median thymidine kinase activity calculated. It was 3.0 pmol/mg/min x % S phase in the HIV-seronegative group and 1.1 pmol/mg/min x % S phase in HIV-infected individuals. The difference in thymidine kinase activity is statistically significant (p = 0.0001). The concentration of TK1 protein in the same extracts was also determined by immunoblotting. A positive correlation (r = 0.74) was observed between TK activity and amount of TK1 protein. The reason for this downregulation of TK is still unknown but may be related to the anergy observed in lymphocytes from HIV-infected persons. The reduced capacity for intracellular phosphorylation of AZT in HIV-infected individuals may be an important factor in the emergence of clinical AZT resistance and should also be accounted for in testing AZT resistance in vitro with PBMCs from healthy blood donors.
...
PMID:Decreased thymidine kinase levels in peripheral blood cells from HIV-seropositive individuals: implications for zidovudine metabolism. 754 7

Zalcitabine (ddC) was the first drug to be approved under the US Food and Drug Administration's (FDA's) accelerated drug approval process. Zalcitabine is a potent nucleoside analogue inhibitor of reverse transcriptase used in the treatment of HIV infection. It is approximately 10-fold more potent than zidovudine (AZT) on a molar basis in vitro. Zalcitabine is well absorbed orally and reaches maximal plasma concentrations within 1 to 2 hours. In humans it is mainly eliminated by renal excretion of unchanged drug, and patients with renal failure may exhibit a prolonged half-life. A variety of clinical trials have evaluated the efficacy of zalcitabine based on improved survival and decreased frequency of opportunistic infections and on a surrogate marker of HIV disease, the CD4 count, or the concentration of an antigen associated with HIV, p24. Alternating zalcitabine therapy with zidovudine therapy was associated with increased CD4+ lymphocyte counts and reduced plasma p24 antigen levels. Zalcitabine can cause peripheral neuropathy (in 17 to 31% of patients), which is dose-related and is completely reversible when the drug is discontinued. Zalcitabine will continue to play a role in chemotherapeutic approaches to HIV.
...
PMID:Zalcitabine. Clinical pharmacokinetics and efficacy. 761 75

Polyribonucleotides (PTMG and PMTI) containing 1-methyl-6-thioguanosine or 1-methyl-6-thioinosine, respectively, as the sole nucleoside component are shown to be potent inhibitors of various strains of HIV-1 and HIV-2 in a number of human lymphocyte and macrophage cell lines in tissue culture as well as in fresh human peripheral blood lymphocytes and macrophages. PMTI and PMTG exhibit potencies in the range of 10(-7)-10(-8) M in these systems. The polynucleotides are active against virus strains resistant to AZT and pyridinone derivatives. Both PMTI and PMTG are synergistic with AZT and with ddI, and both inhibit HIV reverse transcriptase at nanomolar concentrations. The polymers show little or no toxicity in human cell lines at the highest doses tested (100 micrograms/mL, or about 0.2-1 microM). This class of compounds represents a new lead in AIDS therapeutic drug discovery.
...
PMID:Unusual single-stranded polyribonucleotides as potent anti-HIV agents. 765 Jun 78

A nonselective ex vivo assay was used to directly detect and quantify zidovudine (AZT)-resistant human immunodeficiency virus type 1 (HIV-1) in the blood of treated and untreated patients. In contrast to previous reports, drug-resistant virus was detected in peripheral blood mononuclear cells of a few of the patients who had never received AZT. The AZT resistance of HIV-1 isolates from one untreated individual was confirmed by further susceptibility studies in vitro and by the finding of a characteristic mutation (Lys-->Arg at codon 70) in the reverse transcriptase. In patients who were clinically stable while on AZT, HIV-1 titers in plasma and mononuclear cells were generally low but resistant viruses already predominated. In those individuals who were deteriorating despite AZT administration, high levels of viremia were observed, and the resistance phenotype was nearly universal. These findings serve to emphasize the magnitude of the AZT-resistance problem in patients on drug treatment.
...
PMID:Quantitation of zidovudine-resistant human immunodeficiency virus type 1 in the blood of treated and untreated patients. 767 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---