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)

3'-Mercapto-3'-deoxy-TTP was synthesized and tested as DNA chain terminator nucleotide for calf thymus alpha DNA polymerase, E. coli DNA polymerase I (Klenow fragment), terminal deoxyribonucleotidyltransferase (Bollum enzyme) and reverse transcriptase from AMV- and HIV-I-viruses. It was shown that the compound terminates DNA chain elongation by reverse transcriptases selectively and irreversibly. Other tested DNA polymerases do not use this nucleotide analogue as a substrate. 3'-Mercapto-3'-deoxythymidine was tested on lymphoblastoid T-cell line MT-4 with HIV-viruses and shown to suppress viruses as efficiently as 3'-azido-3'-deoxythymidine.
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PMID:[3'-Mercapto-3'-deoxythymidine-5'-triphosphate as a terminator of DNA synthesis catalyzed by RNA-dependent DNA-polymerases]. 171 4

Certain bis(heteroaryl)piperazines (BHAPs) are potent inhibitors of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) at concentrations lower by 2-4 orders of magnitude than that which inhibits normal cellular DNA polymerase activity. Combination of a BHAP with nucleoside analog HIV-1 RT inhibitors suggested that together these compounds inhibited RT synergistically. In three human lymphocytic cell systems using several laboratory and clinical HIV-1 isolates, the BHAPs blocked HIV-1 replication with potencies nearly identical to those of 3'-azido-2',3'-dideoxythymidine or 2',3'-dideoxyadenosine; in primary cultures of human peripheral blood mononuclear cells, concentrations of these antiviral agents were lower by at least 3-4 orders of magnitude than cytotoxic levels. The BHAPs do not inhibit replication of HIV-2, the simian or feline immunodeficiency virus, or Rauscher murine leukemia virus in culture. Evaluation of a BHAP in HIV-1-infected SCID-hu mice (severe combined immunodeficient mice implanted with human fetal lymph node) showed that the compound could block HIV-1 replication in vivo. The BHAPs are readily obtained synthetically and have been extensively characterized in preclinical evaluations. These compounds hold promise for the treatment of HIV-1 infection.
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PMID:Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. 171 88

Previously we raised a rabbit monospecific antibody (C2003) against a synthetic peptide derived from a sequence within the C-terminal portion of the reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1). This sequence is found to be conserved in the predicted amino acid sequence of a related lentivirus, the equine infectious anemia virus (EIAV). It was previously determined that the C2003 antibody could cross-react with native EIAV RT and directly inhibit the DNA polymerase activity of the enzyme. We have now fractionated EIAV RT by immunoaffinity chromatography with immobilized C2003 antibody. The procedure yielded an equimolar mixture of two proteins of 66 and 51 kDa associated with both DNA polymerase and RNase H activities. When the EIAV RT proteins were examined by in situ activity gel assays, polymerase activity was found to be principally associated with the 66-kDa component. The fidelity of DNA synthesis by EIAV RT was found to be equivalent to that of HIV-1 RT and lower than that of AMV RT. These observations indicate that the RTs of EIAV and HIV-1 share similar structural and functional properties.
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PMID:Purification and partial characterization of equine infectious anemia virus reverse transcriptase. 171 86

Arguments are presented leading to the conclusion that two major factors contribute to the potency of inhibition of DNA-polymerase activity by chain-terminating nucleotides. The relative significance of these factors varies with the reaction conditions, particularly with the length of the template and the concentration ratio of enzyme (reverse transcriptase or other DNA polymerase) to primer. It is concluded that potent inhibition of HIV-reverse transcriptase activity under typical in vitro and in vivo conditions arises from different features of the interaction of chain terminators with the enzyme. A new method of testing for the parameter important under in vivo conditions is suggested.
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PMID:Factors contributing to the inhibition of HIV reverse transcriptase by chain-terminating nucleotides in vitro and in vivo. 171 77

Psychotrine dihydrogen oxalate and O-methylpsychotrine sulfate heptahydrate (MP), the salts of isoquinoline alkaloids from ipecac, were found to be potent inhibitors of the DNA polymerase activity of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT). We currently report the results of additional studies designed to characterize the mechanism of inhibition facilitated by MP. The inhibition was noncompetitive with respect to TTP and uncompetitive with respect to poly(rA) and oligo(dT)12-18 (4:1) at low template-primer concentrations but competitive at high concentrations (greater than 200 microM). Identical non-Michaelis-type kinetics were observed when activated DNA was used as the template. The biphasic nature of the double-reciprocal plots and Hill coefficients of less than 1 indicate that MP functions as an allosteric inhibitor of the enzyme which appears to possess multiple active sites that interact in a cooperative (negative) fashion in the presence of the inhibitor. MP was selective for the recombinant HIV-1 RT (p66) utilizing poly(rA) and oligo(dT)12-18 (4:1) as template-primer. Greater inhibition was observed with this template primer as compared with other natural and synthetic template-primers tested. MP had significantly less effect on avian myeloblastosis virus RT as well as mammalian or bacterial DNA and RNA polymerases. Other members of the ipecac class of alkaloids, e.g. emetine hydrochloride, were inactive against all of these enzymes, including HIV-1 RT. Conversely, MP did not inhibit in vitro protein synthesis, a property manifested by all the other ipecac alkaloids tested. Studies conducted with structural analogs revealed that the imine functionality at positions 1' and 2' of MP is the key structural requirement for HIV-1 RT inhibitory activity. Therefore, MP appears to possess unique structural properties that enable interaction with HIV-1 RT in a manner that can be differentiated from other polymerases. Use of these alkaloids for the definition of this viral enzyme-specific topology may lead to the development of therapeutically useful chemotherapeutic agents.
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PMID:Psychotrine and its O-methyl ether are selective inhibitors of human immunodeficiency virus-1 reverse transcriptase. 172 Oct 50

We have constructed a series of plasmids which, when introduced into Escherichia coli, induce the overexpression of soluble wild-type and mutated forms of the reverse transcriptases (RTs) from human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2, respectively). These proteins were analyzed previously for their RNA-dependent DNA polymerase (RDDP) and ribonuclease H (RNase H) activities. In the present study we assayed the different mutant RTs for their DNA-dependent DNA polymerase (DDDP) activity, employing an in situ polyacrylamide gel activity assay. The results indicate that both the RDDP and DDDP catalytic functions of HIV-1 RT mutants are affected similarly by mutations suggesting a high degree of overlap between the catalytic domains involved in both activities. Contrariwise, many of the HIV-2 RT mutants display no correlation between these two DNA polymerase activities, that is, the DDDP activity was not affected by the mutations introduced in the native enzyme in contrast to the RDDP activity. We were thus able to generate mutants of HIV-2 RT that unlike the wild-type RT, are capable of transcribing only DNA and not RNA. The disparity in mutational-catalytic relations between the two HIV-related RTs may reflect a possible difference in the structure and folding properties of the two proteins.
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PMID:The DNA-dependent and RNA-dependent DNA polymerase activities of the reverse transcriptases of human immunodeficiency viruses types 1 and 2. 172 5

Extracts derived from Albizia amara were found to demonstrate activity in a recently developed hplc system designed to detect compounds capable of interacting with DNA. Further investigation led to the procurement of four sets of alkaloid isolates X1-X4 that were found to be macrocyclic pithecolobine alkaloids. All four isolates interacted with calf thymus DNA and were generally cytotoxic with a battery of cultured mammalian cells. As determined with Salmonella typhimurium strain TM677, isolates X1 and X3 were bactericidal, but not mutagenic. Isolate X1 was found to inhibit the catalytic activity of DNA polymerase, RNA polymerase, and HIV-1 reverse transcriptase. With DNA polymerase, the reaction was shown to be inhibited in a manner that was competitive with respect to DNA. In addition, isolate X1 inhibited each of the following: platelet aggregation, human lymphocyte transformation, phorbol-ester-induced chemiluminescence with human granulocytes, and cyclooxygenase activity. Detection of these alkaloids on the basis of their interaction with DNA exemplifies the validity of this approach.
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PMID:Biological activity of novel macrocyclic alkaloids (budmunchiamines) from Albizia amara detected on the basis of interaction with DNA. 172 78

Electron microscopic features of muscle biopsies from 13 human immunodeficiency (HIV)-positive patients who had myopathy while receiving zidovudine (AZT) were compared with biopsies from five patients with HIV-induced myopathy who were not treated with AZT. All specimens showed disorganization of the myofibrillar structures, along with a varying degree of nemaline (rod) bodies, vacuolization, inflammation, and endothelial tubuloreticular profiles. One untreated and all AZT-treated patients had cytoplasmic bodies, which in the latter were abundant, large, and irregular. Two untreated patients had a peculiar osmiophilic destruction of the muscle fibers, with numerous tubuloreticular profiles in the endothelial cells and brisk inflammation that included lymphoplasmatoid cells. The AZT-treated group had ubiquitous abnormal mitochondria that complemented the presence of ragged red fibers seen by light microscopy. There was subsarcolemmal proliferation of mitochondria, with marked variation in size and shape and proliferation or disorganization of their cristae. Paracrystalline inclusions were seen in one patient. Blind re-examination of the electron micrographs showed abnormal mitochondria that readily distinguished patients with AZT-associated myopathy from those with untreated HIV-induced myopathy. Immunocytochemistry using antibodies to single- and double-stranded DNA revealed severe reduction of mitochondrial DNA compared with the normal nuclear DNA. Although the myopathies associated with HIV and AZT share common myopathologic features, the mitochondrial abnormalities are unique to the AZT-treated patients. Since mitochondrial DNA is specifically reduced, the structural changes noted on electron microscopy are probably associated with mitochondrial dysfunction. Zidovudine, a DNA chain terminator that inhibits the mitochondrial gamma-DNA polymerase, is toxic to muscle mitochondria.
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PMID:Ultrastructural characteristics and DNA immunocytochemistry in human immunodeficiency virus and zidovudine-associated myopathies. 174 34

Cytomegalovirus (CMV) infection is extremely common in patients with advanced human immunodeficiency virus infection, in whom it can produce a variety of clinical syndromes. Ganciclovir is a guanosine analogue that selectively inhibits CMV DNA polymerase when intracellularly phosphorylated to its active form. In patients with CMV retinitis, induction therapy with ganciclovir results in high rates of clinical and virologic response; maintenance therapy is required to forestall progression of disease. Clinically relevant resistance of CMV to ganciclovir has recently been reported. Decreased phosphorylation of ganciclovir to its active form has been observed in cells infected with resistant strains, suggesting that CMV may encode a ganciclovir-phosphorylating enzyme whose function is deleted by mutation, conferring resistance. Further study is needed to establish the mechanism of resistance and to define the prevalence of resistance in the clinical setting.
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PMID:Clinical use of ganciclovir for cytomegalovirus infection and the development of drug resistance. 184 21

Zidovudine triphosphate inhibits the hepatitis B virus (HBV) DNA polymerase (DNAp) in vitro. Serial measurements of serum HBV DNAp activity and HBV DNA were made in 14 consecutive male homosexual patients starting zidovudine for symptomatic HIV-1 infection. Median duration of treatment was 15 weeks (range 2-72). In the 13 patients with detectable DNAp/DNA pre-treatment, no significant change in either measure of viral replication was observed during the first 16 weeks of treatment compared with the 13 weeks prior to treatment. The lack of response may be due to the opposing effect of immunosuppression, or to a failure of in vivo activity.
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PMID:No effect of zidovudine on hepatitis B virus replication in homosexual men with symptomatic HIV-1 infection. 203 94


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