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)

High levels of unintegrated viral DNA accumulate during human immunodeficiency virus type 1 (HIV-1) infection of CEM T cells. Reinfection of already infected cells is required to attain these levels and reinfection also promotes the development of HIV-induced cytopathology. Rates of virus production, however, are independent of the accumulation of unintegrated viral DNA. Neutralizing antibody added soon after infection reduced viral DNA levels without appreciably affecting the production of cell-free viral p24 antigen or reverse transcriptase activity. Only 50 pM AZT were required to reduce the accumulation of unintegrated viral DNA by 50% in contrast to the 25 nM required to inhibit virus production by 50%. Cytopathology, as measured by number of syncytia in infected cell cultures, was correlated with highly elevated levels of unintegrated viral DNA. The minimal levels of unintegrated viral DNA present constitutively in the persistently infected HCEM cell line were consonant with the absence of cytopathic effects in these cells. These data demonstrate that inhibiting the reinfection of already infected cells modulates cytopathic HIV-1 infection to a form that is persistent and noncytopathic.
...
PMID:Reinfection results in accumulation of unintegrated viral DNA in cytopathic and persistent human immunodeficiency virus type 1 infection of CEM cells. 221 39

Since the first controlled clinical trial of zidovudine (ACT) was terminated in the fall of 1986, much has been learned concerning the use of this agent in the treatment of human immunodeficiency virus (HIV) infection. The recent report of HIV resistance associated with long-term AZT therapy has accelerated the sense of urgency about the development of additional agents for use--either alone or in combination with AZT--against this infection. Several new agents are in various stages of preclinical or clinical evaluation. Some, such as dideoxycytidine, dideoxyinosine, dideoxydidehydrothymidine, azidouridine, and foscarnet, inhibit viral DNA synthesis through inhibition of reverse transcriptase. Other potentially useful agents presumably act at different stages of infection. Soluble CD4, for example, is a soluble form of the receptor to which HIV must bind to infect cells, and castanospermine represents a new class of compounds that block the maturation process of the viral glycoprotein. An apparently more potent and less toxic analogue of the latter agent, N-butyl-deoxynojirimycin, is currently in phase I testing.
...
PMID:New antiretroviral agents in the clinic. 223 36

Zidovudine (AZT) penetrates human monocytes to exert its antiretroviral activity at the level of reverse transcriptase in infected cells. Stimulation of normal human monocytes with lipopolysaccharide (LPS) results in the transcription of interleukin-1 (IL-1) genes, the intracellular accumulation of IL-1 alpha and IL-1 beta precursors, and the subsequent extracellular release of functional IL-1 beta. The present study demonstrates that zidovudine inhibits the extracellular release of IL-1 activity without affecting the generation of intracellular IL-1 or the amount of released IL-1 beta protein. Similar results were observed with monocytes from normal individuals and monocytes from patients with AIDS. Since IL-1 may upregulate the expression of HIV genes in infected cells, the inhibitory effect of zidovudine on the release of functional IL-1 may be relevant for the beneficial effect of the drug in HIV infection.
...
PMID:Zidovudine inhibits functional extracellular monocytic interleukin-1. 235 Apr 46

The two isomers 3'-azido-3'-deoxythymidine 5'-triphosphate (erythro-AZT-TP) and 1-(3'-azido-2',3'-dideoxy-beta-D-xylofuranosyl)thymine 5'-triphosphate (threo-AZT-TP) were studied as inhibitors of the reverse transcriptase activity of avian myelobastosis virus. Kinetic analysis of the (rA)n X (dT)12-18 (a standard template primer complex of polyriboadenylate and oligodeoxythymidylate of indicated length)-directed reaction revealed that erythro-AZT-TP was a competitive inhibitor with respect to dTTP, whereas threo-AZT-TP was a noncompetitive inhibitor. The apparent Ki values, as calculated from Dixon plots, were 0.48 and 5.5 microM, respectively, compared with a Km value for dTTP of about 70 microM. These results indicate that erythro-AZT-TP had an approximately 150-times-higher affinity to the enzyme than dTTP had and that the avian myeloblastosis virus reverse transcriptase had different binding sites for the two isomers.
...
PMID:Different patterns of inhibition of avian myeloblastosis virus reverse transcriptase activity by 3'-azido-3'-deoxythymidine 5'-triphosphate and its threo isomer. 244 Mar 79

The new antiviral agent, azidothymidine (AZT; BW A509U), is currently the only successful drug in use for patients with acquired immunodeficiency syndrome. The effect of this thymidine analog, 3'-azido-3'-deoxythymidine, on the replication of the lymphadenopathy-associated virus strain of the human immunodeficiency virus was evaluated by using susceptible H9 and Jurkat cells. Cells were pretreated with concentrations of drug ranging from 0.5 to 100 microM, infected, and maintained in medium containing drug. Virus production was assayed by reverse transcriptase assays, and virus-specific DNA was analyzed by Southern blots probed with cloned human immunodeficiency virus sequences. At 4 to 8 days postinfection, infected cells without drug reached a peak of reverse transcriptase activity that was sustained. Increasing concentrations of AZT caused increasing delays in virus production; however, replicate cultures at nontoxic levels of the drug (up to 25 microM) eventually produced as much virus as did non-drug-treated infected cells, despite the continued presence of the drug. Levels of intracellular, unintegrated, virus-specific DNA paralleled reverse transcriptase levels. Virus-caused cytopathic effect was likewise delayed in drug-treated cultures. Virus recovered from H9 cultures after 25 microM AZT treatment did not appear resistant to AZT.
...
PMID:Resumption of virus production after human immunodeficiency virus infection of T lymphocytes in the presence of azidothymidine. 244 6

A series of nucleotide homo- and heterodimers [3'-azido-3'-deoxythymidilyl-(5',5')-2',3'-di-deoxy-5' adenylic acid (AZT-P-ddA), 3'-azido-3'-deoxythymidilyl-(5',5')-2', 3'-dideoxy;-5'-adenylic acid, 2-cyanoethyl ester [AZT-P(CyE)-ddA], 3'-azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxy-5'-inosinic acid (AZT-P-ddI), and 3'-azido-3'-deoxythymidilyl-(5',5')-3'-azido-3'-deoxy-5'-thymid ilic acid (AZT-P-AZT)] were synthesized and compared with respect to their anti-HIV and cytotoxic properties to their component monomers in vitro. MT-2 cells were infected with HIV (TM) followed by the addition of drug. The dimers and their respective monomers inhibited HIV-induced syncytia formation, reverse transcriptase production, and the expression of HIV p24 antigen. However, on an equimolar basis, greater anti-HIV potency and enhanced cytotherapeutic indices were observed with the heterodimers when compared with their monomers. Nucleotide dimers, such as AZT-P-ddA, should be actively considered for further evaluation as anti-HIV agents.
...
PMID:Nucleotide dimers suppress HIV expression in vitro. 246 62

Feline immunodeficiency virus (FIV), formerly called feline T-lymphotropic lentivirus, causes an immune deficiency in cats that is very similar to the acquired immune deficiency syndrome in humans (N. C. Pedersen, E. M. Ho, M. L. Brown, and J. K. Yamamoto, Science 235:790-793, 1987). We have examined the reverse transcriptase of this virus to determine whether it is similar enough to the reverse transcriptase of the human immunodeficiency virus type 1 (HIV-1) to enable its use as a model for chemotherapy for acquired immune deficiency syndrome. The FIV reverse transcriptase is similar to that of HIV-1 in sensitivity to the noncompetitive inhibitor phosphonoformate (Ki, 0.3 microM) and relative insensitivity to phosphonoacetate. This enzyme was also sensitive to two competitive inhibitors, the 5'-triphosphates of 2', 3'-dideoxythymidine (Ki, 3.4 nM) and 3'-azido-3'-deoxythymidine (AZT; Ki, 6.2 nM). The ratios of Ki/Km for these two competitive inhibitors are similar to the ratios calculated from previously reported data for the HIV-1 enzyme assayed under identical conditions. In contrast, the FIV enzyme is different from the reverse transcriptase of avian myeloblastosis virus in sensitivity to those inhibitors. The replication of FIV in Crandell feline kidney cells was inhibited by AZT; virus production was inhibited more than 95% by 1.0 microM AZT.
...
PMID:Feline immunodeficiency virus, a model for reverse transcriptase-targeted chemotherapy for acquired immune deficiency syndrome. 247 68

Three chondroitin sulphates and five chondroitin polysulphates, with molecular weights ranging from 3000 to 30,000 daltons, were evaluated applying the MT-4 cell-culture assay for inhibition of HIV-1 replication. These results were compared with those obtained with compounds of known in vitro antiretroviral activity, namely, dermatan sulphate, heparin, dextran sulphate, pentosan polysulphate, zidovudine (AZT) and suramin. Chondroitin polysulphate with a molecular weight (MW) of 9000 daltons (CPS 9000) was the most effective polyanionic compound studied. In contrast with zidovudine, this CPS 9000 was not toxic for MT-4 cells up to a concentration of 500 micrograms/ml. Moreover, CPS 9000 is highly specific for inhibition of HIV-1 reverse transcriptase.
...
PMID:In vitro anti-HIV-1 activity of chondroitin polysulphate. 247 44

Human immunodeficiency virus (HIV) isolates with reduced sensitivity to zidovudine (3'-azido-3'-deoxythymidine, AZT) from individuals with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex were studied to determine the genetic basis of their resistance. Most were sequential isolates obtained at the initiation of and during therapy. Comparative nucleotide sequence analysis of the reverse transcriptase (RT) coding region from five pairs of sensitive and resistant isolates identified three predicted amino acid substitutions common to all the resistant strains (Asp67----Asn, Lys70----Arg, Thr215----Phe or Tyr) plus a fourth in three isolates (Lys219----Gln). Partially resistant isolates had combinations of these four changes. An infectious molecular clone constructed with these four mutations in RT yielded highly resistant HIV after transfection of T cells. The reproducible nature of these mutations should make it possible to develop rapid assays to predict zidovudine resistance by performing polymerase chain reaction amplification of nucleic acid from peripheral blood lymphocytes, thereby circumventing current lengthy HIV isolation and sensitivity testing.
...
PMID:Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). 247 83

The nucleoside analogue 1-(2,3-dideoxy-beta-D-glycero-pent-2-enofuranosyl)thymine (d4T, 1) was prepared by ring opening of the 3',5'-anhydro compound 5. This method has been refined such that it can be used to prepare d4T on a large scale. The triphosphate of d4T was also synthesized from 1 in order to examine the mode of action. The in vitro inhibitory activity of d4T was found to be comparable to that of AZT in HIV-infected CEM cells. The triphosphate of d4T (8) and that of AZT inhibited the HIV reverse transcriptase with poly(rA):oligo(dT) as the template:primer with Ki values of 0.032 and 0.007 microM, respectively. The in vitro toxicity of d4T against normal human hematopoietic progenitor cells (CFU-GM) was measured in comparison to AZT. While d4T reduces colony-forming units by 50% at a concentration of 100 microM, it takes only 1 microM AZT to have a similar toxic effect. With erythrocyte burst forming units (BFU-E) the in vitro toxicities for d4T and AZT have comparable ID50 values of 10 and 6.7 microM, respectively.
...
PMID:1-(2,3-Dideoxy-beta-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent. 253 41


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

---