Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using a computer-assisted molecular modeling protocol, we have completed the three-dimensional structures of HIV-1 reverse transcriptase and the Klenow fragment of DNA polymerase I based on the C alpha crystal coordinates of the individual enzymes. The two model-built structures were then used to compare the electrostatic potential contours and analyze the spatial positions of residues conserved in the catalytic domains of the two enzymes. In spite of rather weak sequence similarity and different folding patterns between the DNA-dependent DNA polymerase (pol I) and the RNA-dependent DNA polymerases (RT), we have noted the occurrence of identical or similar residues at common spatial positions in pol I and RT in a three-dimensional context. The homologous residues present at equivalent spatial position in the Klenow fragment and the p66 subunit of HIV-1 RT may therefore imply their functional similarity. Furthermore, these conserved residues may represent a similar structure-function feature in all polymerases.
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PMID:A computer-assisted analysis of conserved residues in the three-dimensional structures of the polymerase domains of Escherichia coli DNA polymerase I and HIV-1 reverse transcriptase. 750 63

3'-Deoxy-3'-azidothymidine (AZT) has been shown to synergistically inhibit the replication of human immunodeficiency virus type 1 (HIV-1) in cell culture when combined with several other 2',3'-dideoxynucleoside analogs. In an effort to understand the biochemical mechanism of this synergy, we have examined the effect of combinations of the 5'-triphosphate of AZT (AZT-TP) with either ddCTP, ddATP, or the 5'-triphosphate of the carbocyclic analog of 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir) on both the RNA-directed and DNA-directed DNA polymerase activity of HIV-1 reverse transcriptase. Kinetic studies, which evaluated the ability of these combinations to competitively inhibit the enzyme, showed that AZT-TP could not bind to the enzyme with either the RNA or DNA template at the same time as either of the other three inhibitors. None of these analogs could affect the incorporation of another analog into the DNA chain by the HIV-1 reverse transcriptase. These results indicated that synergistic inhibition of the HIV-1 reverse transcriptase is not responsible for the synergistic antiviral activity seen in cell culture with combinations of these nucleoside analogs.
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PMID:Lack of synergy in the inhibition of HIV-1 reverse transcriptase by combinations of the 5'-triphosphates of various anti-HIV nucleoside analogs. 750 13

Thiobenzimidazolone (TIBO) derivatives are known inhibitors of the DNA polymerase activity of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). The effect of a TIBO derivative ((+)-S-4,5,6,7-tetrahydro-9-chloro-5- methyl-6-(3-methyl-2-butenyl)-imidazol[4,5,1-jk]1,4-benzodiazapine -2-thione ) on the DNA strand transfer reaction catalyzed by HIV-1 RT (which is a function of both the DNA polymerase and RNase H activities) was investigated by delineating the effect of the drug on the constitutive DNA polymerase and RNase H activities) was investigated by delineating the effect of the drug on the constitutive DNA polymerase and RNase H activities. Single nucleotide incorporation on template-primer 1 was used to study the DNA polymerase activity of HIV-1 RT while template-primer 2 was used to study the effect of TIBO on the RNase H activity (polymerase independent). The drug was found to decrease the amplitude of the presteady-state burst when preequilibrated with the enzyme-substrate complex besides decreasing the steady-state rate of single nucleotide incorporations. In the absence of preincubation, TIBO did not affect the burst amplitude but decreased the steady-state rate after the pre-transient phase. This suggested that binding of TIBO to RT was affected by the presence of template-primer and required dissociation of the enzyme from the template-primer for effective binding. The polymerase-independent RNase H activity was activated in the presence of TIBO. The effect of TIBO on the overall process of DNA strand transfer is a balance between its inhibition of the polymerase activity and its activation of the RNase H activity.
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PMID:Effect of a thiobenzimidazolone derivative on DNA strand transfer catalyzed by HIV-1 reverse transcriptase. 750 39

The reverse transcriptase (RT) of equine infectious anemia virus (EIAV) shares sequence similarity with the RTs of other lentiviruses, particularly with the RTs of human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2, respectively), the causative agents of acquired immunodeficiency syndrome (AIDS). There is a 41-42% sequence identity between EIAV RT and both HIV RTs (which have 61% sequence identity to each other). We have compared the enzymic properties of EIAV RT with those of HIV-1 RT. Several aspects of the activities of EIAV RT differ from the corresponding activities of HIV-1 RT. There are significant differences in the inhibition of the DNA polymerase activities by the deoxynucleoside triphosphate analogs, 3'-azido-2,3'-dideoxythymidine triphosphate, dideoxyTTP and dideoxyGTP and by the nonnucleoside inhibitor, tetrahydroimidazo[4,5,1-jk-1,4]benzodiazepin-2-(1H)-one and thione; in the dependence of DNA polymerase and RNase H activities on pH; in the inhibition of the DNA polymerase activities by the thiol-specific reagent N-ethylmaleimide; in the specific DNA polymerase activity; in the inhibition of the ribonuclease H activity by the zinc chelator orthophenanthroline. However, there are several cases in which EIAV RT and HIV-1 RT are more similar than was previously found for HIV-1 RT and HIV-2 RT. These include the Km values for the DNA polymerase activities, the heat stability of the DNA polymerase functions and the specific activity of the RNase H function.
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PMID:The catalytic properties of the reverse transcriptase of the lentivirus equine infectious anemia virus. 750 81

The unusually high frequency of misincorporation by HIV-1 reverse transcriptase (HIV RT) is likely to be the major factor in the rapid accumulation of viral mutations in AIDS, especially in the env gene. To investigate the ability of HIV RT to copy the env gene, we subcloned an HIV env gene fragment into a single-stranded DNA vector and measured the progression of synthesis by HIV RT. We observed that HIV RT, but not RT from avian myeloblastosis virus, DNA polymerase-alpha or T7 DNA polymerase, pauses specifically at poly-deoxyadenosine stretches within the env gene. The frequency of bypassing the polyadenosine stretches by HIV RT is enhanced by increasing the ratio of enzyme to template. We measured the fidelity of DNA synthesis within a segment of the hypervariable region 1 of the env gene (V-1) containing a poly-deoxyadenosine sequence by repetitively copying the DNA by HIV RT, and then cloning and sequencing the copied fragments. We found that 27% of the errors identified in V-1 sequence were frameshift mutations opposite the poly-adenosine tract, a site where strong pausing was observed. Pausing of HIV RT at the polyadenosine tract could be enhanced by either distamycin A or netropsin, (A-T)-rich minor groove binding peptides. Moreover, netropsin increases the frequency of frameshift mutations in experiments in which HIV RT catalyzes gap filling synthesis within the lacZ gene in double-stranded circular M13mp2 DNA. These combined results suggest that the enhanced mutation frequency may be due to increased pausing at netropsin-modified polyadenosine tracts. Therefore, netropsin and related A-T binding chemicals may selectively enhance frameshift mutagenesis induced by HIV RT and yield predominantly non-viable virus.
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PMID:Mutagenicity and pausing of HIV reverse transcriptase during HIV plus-strand DNA synthesis. 751 Mar 88

Activity against human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) in the organic extract of the Red Sea sponge Toxiclona toxius was traced by us to five novel natural compounds, namely toxiusol [1], shaagrockol B [3], shaagrockol C [4], toxicol A [6], all of which are sulfated hexaprenoid hydroquinones, and toxicol B [7], the p-hydroquinone derivative of compound 6. The hydrolysis of the two sulfated compounds 1 and 4 yielded the corresponding hydroquinones designated as compounds 2 and 5, and further oxidation of compound 7 afforded the corresponding p-quinone derivative, compound 8. All compounds exhibited inhibitory activity of both DNA polymerizing functions of HIV-1 RT but failed to inhibit the RT-associated ribonuclease H activity. Toxiusol [1] was found to be the most potent inhibitor of the RNA-dependent DNA polymerase function (with 50% inhibition obtained at 1.5 microM and 95% inhibition at 4.6 microM), whereas the DNA-dependent DNA polymerase was significantly less sensitive to the inhibitor (with 50% inhibition achieved at 6.6 microM and 95% inhibition only at 41.6 microM). The fact that compound 1 discriminates between the two DNA polymerase activities of the RT offers new prospects for developing potent and highly specific anti-RT compounds, since the RNA-dependent DNA polymerase activity of RT is the only unique function that is not expressed at significant levels in uninfected mammalian cells.
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PMID:Hexaprenoid hydroquinones, novel inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. 751 Jul 86

The natural product of the Red Sea sponge Verongia sp., identified as 3,5,8-trihydroxy-4-quinolone, was found to be a potent inhibitor of the RNA-directed DNA synthesis of the reverse transcriptases (RTs) of human immunodeficiency viruses type 1 and type 2 (HIV-1 and HIV-2, respectively). This inhibition was unaffected by the nature of the primer template used for DNA synthesis. The DNA-dependent DNA polymerase activity was inhibited to a lesser extent, whereas the ribonuclease H (RNase H) function associated with both HIV RTs was only slightly inhibited. The inhibition by the trihydroxyquinolone is reversible and noncompetitive with respect to both substrates--dTTP and the template primer poly(rA)n.oligo(dT)12-18. The inhibitor binds HIV-1 RT with a high affinity (Ki = 0.46 microM). This compound was shown also to inhibit the catalytic activities of the RT of murine leukemia virus, establishing the general inhibitory effect on retroviral RTs. Introductions of acetyl or methoxy moieties at positions with potential activity have generated three synthetic analogs of the natural compound. Only one analog, 5,8-dimethoxy-4-quinolone, exhibited an inhibition potency similar to that of the unmodified compound. Analysis of the three analogs has led us to the conclusion that the hydroxyl group at the ortho position to the carbonyl group in the pyridinone ring is a key structural element for the inhibitory activity. Thus, it could well be that the inhibitor interacts with the enzyme through a hydrogen bond of this hydroxyl group. We hope that the identification of the inhibitory site of the compound might be an important step toward the rational design of new potent anti-HIV RT drugs.
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PMID:3,5,8-Trihydroxy-4-quinolone, a novel natural inhibitor of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2. 751 Sep 44

Inhibitory effects of 2'-deoxy-L-thymidine 5'-triphosphate (L-dTTP), the enantiomer of the natural substrate D-dTTP, on the activity of mammalian DNA polymerases alpha, beta and gamma, Escherichia coli DNA polymerase I and human immunodeficiency virus 1 (HIV-1) reverse transcriptase were examined. When poly(rA)n-oligo(dT)12-18 was used as the template-primer, L-dTTP showed remarkable inhibitory effect on HIV-1 reverse transcriptase in competitive fashion with respect to the substrate dTTP. In contrast, L-dTTP did not inhibit DNA polymerases alpha and was slightly inhibitory to DNA polymerase beta. These results suggest that the nuclear DNA polymerases alpha and beta showed high specificity for the substrate with the natural configuration of the sugar moiety, D-dTTP, exhibiting little or no ability to recognize L-dTTP, whereas HIV-1 reverse transcriptase essentially lacked the ability to differentiate the D- and L-sugar moieties.
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PMID:Chiral discrimination of enantiomeric 2'-deoxythymidine 5'-triphosphate by HIV-1 reverse transcriptase and eukaryotic DNA polymerases. 751 92

The human immunodeficiency virus type 1 (HIV-1) is the etiologic agent of AIDS. Replication of this virus requires the activity of a retrovirus encoded RNA-dependent DNA polymerase, or reverse transcriptase (RT). HIV-1 RT is required for the synthesis of the double-stranded proviral DNA from the single-stranded retroviral RNA genome. HIV-1 RT has two subunits of 66 kDa and 51 kDa. The 66-kDa subunit contains the DNA polymerase and RNase H domains whereas the 51-kDa subunit, obtained by proteolytic maturation of the former subunit, has only the DNA synthetic activity. Two recently reported crystal structures of HIV-1 RT have revealed the very asymmetric structure of this molecule. In addition to providing information concerning the mechanism of nucleic acid polymerization, biochemical and biophysical studies of this enzyme are providing key insights for the design of selective antiviral agents. The multiple activities displayed by reverse transcriptase in the replication of the retroviral genome ensure that this enzyme will remain at the forefront of antiviral strategies in the fight against AIDS and other retrovirus-related pathologies.
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PMID:The reverse transcriptase of HIV-1: from enzymology to therapeutic intervention. 751 43

Structures of the 31-kilodalton catalytic domain of rat DNA polymerase beta (pol beta) and the whole 39-kilodalton enzyme were determined at 2.3 and 3.6 angstrom resolution, respectively. The 31-kilodalton domain is composed of fingers, palm, and thumb subdomains arranged to form a DNA binding channel reminiscent of the polymerase domains of the Klenow fragment of Escherichia coli DNA polymerase I, HIV-1 reverse transcriptase, and bacteriophage T7 RNA polymerase. The amino-terminal 8-kilodalton domain is attached to the fingers subdomain by a flexible hinge. The two invariant aspartates found in all polymerase sequences and implicated in catalytic activity have the same geometric arrangement within structurally similar but topologically distinct palms, indicating that the polymerases have maintained, or possibly re-evolved, a common nucleotidyl transfer mechanism. The location of Mn2+ and deoxyadenosine triphosphate in pol beta confirms the role of the invariant aspartates in metal ion and deoxynucleoside triphosphate binding.
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PMID:Crystal structure of rat DNA polymerase beta: evidence for a common polymerase mechanism. 751 81


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