Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This report describes the use of a recombinant murine retrovirus encoding beta-galactosidase (PLJ beta-gal retrovirus) to study the antiretroviral activity of zidovudine (AZT) and other nucleoside analogs. The PLJ beta-gal virus permits the rapid and unequivocal identification of individual virus-infected cells arising from a single cycle of viral replication. With this model system, AZT is shown to completely and irreversibly prevent retrovirus infection of proliferating cell lines as measured by a lack of reporter gene expression. On the other hand, AZT is less effective in protecting growth-arrested cells from retroviral infection. Recombinant retroviruses such as the PLJ beta-gal virus are potentially useful reagents for the identification and characterization of antiretroviral compounds.
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PMID:Use of recombinant retroviruses to characterize the activity of antiretroviral compounds. 192 Jun 37

A number of nucleosides with anti-human immunodeficiency virus (HIV) activity were evaluated in two colorimetric (beta-galactosidase) assays for induction of the SOS response in Escherichia coli. 3'-Azido-3'-deoxythymidine (azidothymidine; AZT), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyguanosine (ddG), and 2',3'-dideoxyinosine (ddI) induced cell filamentation (sulA) and prophage lambda in well-agar diffusion and liquid microsuspension assays. AZT was approximately 100 times more potent than the dideoxypurine nucleosides, inducing sulA at less than 100 ng/ml. 2',3'-Dideoxythymidine (ddT) and 2',3'-dideoxy-2',3'-didehydrothymidine (D4T) induced sulA at 100 to 1,000 micrograms/ml, while 2',3'-dideoxycytidine (ddC) weakly induced prophage lambda. Activity relationships thus were AZT greater than ddA greater than or equal to ddI greater than or equal to ddG greater than ddT = D4T greater than ddC. ddA and ddI had equivalent activities in agar diffusion assays, but different activity profiles were observed in liquid microsuspension assays. The differences may be related to drug metabolism. AZT and ddA showed marginal effects in a DNA repair (preferential toxicity) assay in which E. coli WP2 and CM871 uvrA recA lexA were used. Furthermore, none of the agents was able to preferentially inhibit Bacillus subtilis M45 recA relative to wild-type strain H17. These data suggest that AZT and the dideoxynucleosides do not cause DNA lesions that are repairable by excision repair and/or error-free postreplication repair processes. Rather, the SOS response appears to be induced by DNA chain termination leading to the inhibition of DNA replication. Bacterial assays for induction of the SOS response may be useful as simple, rapid prescreens for the discovery of new anti-HIV agents. Moreover, such assays may provide an additional parameter in the evaluation of agents with demonstrated activity against HIV and other retroviruses.
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PMID:Induction of the SOS response in Escherichia coli by azidothymidine and dideoxynucleosides. 211 27

The science of antiviral research was well advanced when HIV/AIDS appeared as a major new virus disease in the early 1980s. The first effective antiviral compound (AZT, azidothymidine, zidovudine) was already among the library of compounds screened and was promptly reported to be a specific inhibitor of retroviruses, including HIV. Due to the pivotal role of AZT in HIV treatment, this review summarizes the most known effects -some of which are toxic side effects- induced by AZT a drug which is still used in the combined therapy of HIV-infected patients. Among the toxic side effects, a severe bone marrow toxicity manifested as anemia, neutropenia and siderosis, and caused by inhibition of heme and globin synthesis together with a general derangement of iron supply, have been reported. In this regard, we proved that while AZT and its monophosphorylated derivative AZTMP were unable to chelate iron, the triphosphate form AZTTP displayed a significant capacity to remove iron from transferrin. Moreover, we have previously demonstrated that AZT-exposed K562 cells showed an increase of transferrin receptors located on the cell membrane without affecting their biosynthesis, but slowing down their endocytotic pathway. Interestingly, literature data report the impairement of glycosylation reactions by AZT. Indeed, we have shown that AZT-treated K562 cells exhibited a reduced sialylation of proteins and lipids, and a strong inhibition of alpha,(2-->8) sialyltransferase activity while beta,(1-->4)galactosyltransferase and beta-galactosidase activities were significantly increased. These latter observations could be of clinical relevance since alterations of intracellular and cell surface carbohydrate expression and composition, often are associated with several diseases. However, contrarily to previous reports by other authors on AZT as an inhibitor of plant and bacterial toxins activity, we have demonstrated that AZT not only did not inhibit saporin toxicity, but even increased the cytotoxic activity of this plant toxin on K562 cells. Furthermore, the review enlightens the potential utilization of AZT as a tool in proteomics since in the recent years several genes responding to this drug have been identified in different cell lines. We have shown, for the first time, an over-expression of two proteins (PDI-A3 and sthatmin), and a full repression of two others (HSP-60 and SOD1) in AZT-exposed K562 cells. At present, we are investigating if the above reported alterations are a general feature of AZT-treatment of cultured cells, or they represent a peculiar characteristic of a specific cell line. Finally, the paper reviews a number of novel methodologies aimed at enhancing the AZT plasma levels and its bioavailability in all human organs in order to improve its therapeutic efficacy against HIV infection. These new possibilities, namely the AZT prodrug strategy, the AZT transdermal delivery and the targeted brain delivery, are yet not in use for humans but they are under experimental studies.
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PMID:AZT: an old drug with new perspectives. 1869 Aug 75