Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of nucleoside 5'-phosphonates and nucleoside 5'-methylphosphonates were synthesised, to study their ability to inhibit reproduction of HIV-1. Three compounds, 5'-hydrogen phosphonates of 3'-azido-2',3'-dideoxythymidine (AZT-HP, IVc), 3'-fluoro-2',3'-dideoxythymidine (FLT-HP, IVa) and 2',3'-dideoxyadenosine (ddA-HP, I), exhibit potent anti-HIV-1 activity with selectivity indices similar to or better of those of their parent nucleosides.
Mol Biol (Mosk)
PMID:[New 5'-phosphonates, modified through the nucleoside sugar residue, as inhibitors of HIV replication]. 140 17

Inhibition of HIV-1- or HIV-2-induced cytopathicity and (Moloney) murine sarcoma virus (MSV)-induced cell transformation by amino acid and amino alcohol adducts of either 3'-azido-2',3'-dideoxythymidine 5'-monophosphate (AZTMP) or 5'-hydrogenphosphonate (AZTHP) were investigated. Both types of nucleotide adducts inhibited replication of HIV-1 and HIV-2 in MT-4 cells at a 1.5- to 3-fold higher EC50 (50% effective concentration) than AZT; and, also, selectivity indexes of these adducts were approximately 1.5 to 3-fold lower than that of AZT. The activity of the AZTMP and AZTHP adducts against MSV-induced transformation of C3H/3T3 cells was equal to or only slightly inferior than that of AZT, but their toxicity was 10-fold lower, so that their selectivity indexes were 2- to 7-fold higher. The nature of the aminoacyl component of the adducts significantly influence the antiretroviral activity of the test compounds.
Mol Biol (Mosk)
PMID:[Adducts of 3'-azido-2,3'-dideoxythymidine 5'-phosphate or 5'-phosphonate as inhibitors of cytopathic effect and transformation of cells under the influence of retroviruses in cell culture]. 147 Jan 77

The proviral burden of peripheral blood lymphocytes in 29 patients infected with human immunodeficiency virus type-1 (HIV-1) was estimated using a polymerase chain reaction method which we recently refined. The mean numbers of HIV-1 provirus in eight patients with AIDS and AIDS-related complex treated with zidovudine (AZT), in 10 asymptomatic patients treated with AZT, and in 11 asymptomatic untreated patients were 892, 436, and 406 copies in 1 x 10(5) CD4- T lymphocytes, respectively. These results demonstrate that patients may have more HIV-1 provirus copies in an advanced than early stage of disease, and that the fraction of the infected lymphocytes is much higher than previously thought, especially in asymptomatic patients. There was no difference in the viral burden in CD4+ T lymphocytes regardless of whether AZT had been administered or not. These findings validate the method used here to quantitate HIV-1 provirus DNA and confirm that AZT is not effective in reducing the amount of provirus DNA in lymphocytes.
Mol Cell Probes 1991 Apr
PMID:Quantitative estimation of human immunodeficiency virus type-1 provirus in CD4+ T lymphocytes using the polymerase chain reaction. 183 Jan 29

One variant, aphhs-3 was previously isolated based on a hypersensitivity to nontoxic concentrations of aphidicolin, a specific inhibitor of DNA polymerases-alpha and delta. This variant was found to be more sensitive to temperatures above 35 degrees C and to 10 microM of 3'-azido-3'-deoxythymidine (zidovudine, azidothymidine, or AZT) than the parental 743x cells. DNA polymerase activities in the cell extract or in the partially purified fraction by DEAE-cellulose (DE52) anion exchange column from aphhs-3 were active at 40 degrees C. No significant differences in deoxynucleoside triphosphate pools were observed at 34 degrees C for both the parental 743x and aphhs-3 cells. Revertants were isolated at 39 degrees C: six revertants (aphhs-3-tr1 through aphhs-3-tr6) were obtained without aphidicolin; one revertant aphhs-3-tar (the tar clone) was selected in aphidicolin (0.12 microM). The hypersensitivity to aphidicolin (Aphhs) and AZT (AZThs) was cosegregated in the revertant aphhs-3-tr5 (the tr5 clone), while the tar clone was not AZThs. There was a similar increase in the specific activity of 3H-labeled DNA in all cell lines after additions of [3H]AZT or [3H]thymidine. Additions of purine or pyrimidine arabinosides (araT, araC, and araA) to all cell lines resulted in a similar cytotoxicity, suggesting the anabolism of dTTP was not defective in the tr5 clone. The spontaneous mutation rate at the hypoxanthine-guanine phosphoryltransferase locus using replating techniques and 6-thioguanine resistance selection was less than or equal to 5 x 10(-7), 2.2 x 10(-6), or 1.3 x 10(-6) per generation for the tr5, 743x, or tar cell lines, respectively. Most importantly, DNA polymerase activities in the cell extract of the revertant tr5 clone were inhibited by 0.5 microM AZTTP. In contrast, no inhibition was observed in those of the parental 743x and revertant tar cells. The cosegregation of both Aphhs and AZThs in the tr5 revertant suggests that these two phenotypes may be a result of the same mutational event.
Somat Cell Mol Genet 1991 Jan
PMID:Mutants from V79 fibroblasts exhibiting hypersensitivity to aphidicolin and 3'-azido-3'-deoxythymidine. 190 Jan 32

The phenomenon of resistance to azidothymidine during the infection of human immunodeficiency virus (HIV) is reviewed. Different aspects of AZT resistance, including biological and virological characteristics of resistant HIV isolates, genetical mechanisms of resistance, cross-resistance to other nucleoside analogs and non-nucleoside inhibitors, are analyzed. The role of target cells in AZT resistance is also discussed.
Mol Biol (Mosk)
PMID:[Resistance to azidothymidine in human immunodeficiency virus (HIV) infection]. 751 84

The locations of HIV-1 RT nucleoside and non-nucleoside inhibitor-binding sites and inhibitor-resistance mutations are analyzed in the context of the three-dimensional structure of the enzyme and implications for mechanisms of drug inhibition and resistance are discussed. In order to help identify residues that may play a role in inhibitor binding, solvent accessibilities of amino acids that comprise the inhibitor-binding sites in the structure of HIV-1 RT complexed with a dsDNA template-primer are analyzed. While some mutations that cause resistance to nucleoside analogs, such as AZT, ddI, and ddC, are located near enough to the dNTP-binding site to directly interfere with binding of nucleoside analogs, many are located away from the dNTP-binding site and more likely confer resistance by other mechanisms. Many of the latter mutations are located on the surface of the DNA-binding cleft and may lead to altered template-primer positioning or conformation, causing a distortion of the geometry of the polymerase active site and consequent discrimination between normal and altered dNTP substrates. Other nucleoside analog-resistance mutations located on the periphery of the dNTP-binding site may exert their effects via altered interactions with dNTP-binding site residues. The structure of the hydrophobic region in HIV-1 RT that binds non-nucleoside inhibitors, for example, nevirapine and TIBO, has been analyzed in the absence of bound ligand. The pocket that is present when non-nucleoside inhibitors are bound is not observed in the inhibitor-free structure of HIV-1 RT with dsDNA. In particular it is filled by Tyr181 and Tyr188, suggesting that the pocket is formed primarily by rotation of these large aromatic side-chains. Existing biochemical data, taken together with the three-dimensional structure of HIV-1 RT, makes it possible to propose potential mechanisms of inhibition by non-nucleoside inhibitors. One such mechanism is local distortion of HIV-1 RT structural elements thought to participate in catalysis: the beta 9-beta 10 hairpin (which contains polymerase active site residues) and the beta 12-beta 13 hairpin ("primer grip"). An alternative possibility is restricted mobility of the p66 thumb subdomain, which is supported by the observation that structural elements of the non-nucleoside inhibitor-binding pocket may act as a "hinge" for the thumb.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1994 Oct 28
PMID:Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. 752 66

3'-Azido-2',3'-dideoxythymidine (azidothymidine; AZT) induces bone marrow toxicity in patients chronically given therapeutic doses of drug and is tumorigenic in rodents, inducing squamous cell tumors in vaginal tissues of mice and rats. In the study reported here, we explored the incorporation of AZT into specific regions of mammalian chromosomal DNA. CHO cells were exposed to AZT for 4 h, allowed to complete at least one cell cycle, and then arrested in metaphase with colchicine. Regions of concentrated AZT incorporation were identified in individual metaphase chromosomes by immunohistochemistry using antiserum specific for AZT and a secondary antiserum with a streptavidin--Texas red end point. These studies demonstrated that most of the intensely staining regions were chromosomal ends or telomeres. When 18 metaphases were examined, all telomeres but one (39 of 40) were positive at least once. Using an anti-Z-DNA antibody, chromosomal regions containing DNA in Z conformation were also localized by immunohistochemistry using a rhodamine-conjugated secondary antibody. When metaphase chromosome spreads were stained for either AZT or Z-DNA, ideograms showing localization of AZT (18 metaphases) and DNA in Z configuration (26 metaphases) were drawn for every chromosome of each metaphase examined. These ideograms demonstrated that 60% of the regions that stained positive for AZT were also positive for Z-DNA. Furthermore, slides incubated with both antibodies, using streptavidin--Texas red to identify AZT and fluorescein to identify Z-DNA, confirmed colocalization of the two markers. Additional experiments exploring the induction of chromatin bridges in AZT-treated cells suggest that the analogue may be able to bind to and disrupt the normal functioning of telomeric DNA.
Mol Carcinog 1993
PMID:Preferential incorporation of 3'-azido-2',3'-dideoxythymidine into telomeric DNA and Z-DNA-containing regions of Chinese hamster ovary cells. 839 98

A total of seven steroidal prodrugs of AZT were synthesized and tested in vitro for their anti-HIV activity. Three of them were steroidal carboxylic esters prepared from steroidal 17 beta-carboxylic acids and AZT. The remaining four were alkyl steroidal phospho-triesters of AZT. These prodrugs were synthesized using known procedures. Preliminary results of in vitro anti-HIV activity screening showed that all of these prodrugs were active against HIV. While carboxylic esters showed comparable anti-HIV activity to that of AZT, phosphotriesters were less active than AZT. The therapeutic indices of all these prodrugs are comparable to that of AZT.
Cell Mol Biol (Noisy-le-grand) 1995
PMID:Synthesis and anti-HIV activity of steroidal prodrugs of 3'-azido-3'-deoxythymidine (AZT). 857 37

The dideoxynucleoside analogue 2',3'-dideoxyinosine (ddI) has been used in the clinic as an alternative drug to zidovudine (AZT) in the treatment of patients with the acquired immunodeficiency syndrome (AIDS). However, it shows significant and variable toxicity in patients. It is known that various dideoxynucleoside analogues can cause the termination of the DNA chain following incorporation of the corresponding triphosphate metabolite by the polymerases. In the case of ddI, the presumed active metabolite is 2',3'-dideoxyadenosine 5'-triphosphate (ddATP). In order to understand the molecular basis for the toxicity of ddI, we evaluated the relationship between the intracellular formation of ddATP, its incorporation into cellular DNA and the effects on the growth of U937 cells, a human monocytoid cell line. Dideoxyinosine was not significantly toxic to U937 cells at concentrations as high as 500 microM in a 72 hrs. growth inhibition assay. The results of the uptake of 3HddI in this cell line showed a proportional increase in total metabolites with increasing concentrations of the drug (1-20 microM) after a 24 hrs. exposure. Incubation with 10 microM 3HddI resulted in the formation of low levels of ddATP within a period of 2 hrs. A significant amount of ddI-derived radioactivity was found in both DNA and RNA after exposure to 10 microM 3HddI for 24 to 72 hrs. However, no evidence of incorporation of ddATP into the cellular DNA fraction was obtained in these experimental conditions. Therefore, the lack of significant toxicity of ddI to U937 cells can be explained, at least in part, by its inability to incorporate ddATP into its cellular DNA at the doses studied.
Cell Mol Biol (Noisy-le-grand) 1995
PMID:Uptake and distribution of 2',3'-dideoxyinosine and its derivatives in a human monocytoid cell line. 857 39

We have developed versatile synthetic routes that afford metal-free macrocycles containing different functionalities in their framework. Novel oxaziridine and amide containing macrocycles were synthesized, and the metal complexes of the latter were also prepared. A series of theophilline and thymidine side-arm containing podands as well as macrocycles were obtained employing the same methodology. The primary anti-viral tests of these synthetic compounds for anti-HIV-1 activity was carried out using the XTT-based cytopathicity assay (CEM-SS cells) with AZT as positive control. It was found that the nature of the macrocyclic headgroups affected the anti-HIV-1 activity. Heteroatom containing macrocyclic headgroups displayed activity in the micromolar range. Metal complexation did not enhance the activity and side-arm substitution resulted in inactive compounds. Cell viability determined in both Jurkat and CEM-SS cells was strongly dependent on the structure of the macrocyclic framework. The oxaziridine moieties in the macrocycle were highly toxic to CEM-SS and less toxic to Jurkat cell lines, while amide containing macrocycles were toxic to neither.
Cell Mol Biol (Noisy-le-grand) 1995
PMID:Synthesis, activity and toxicity of novel macrocyclic ligands against HIV-1 in Jurkat and CEM-SS cell lines. 857 52


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