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

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Viral resistance limits the value of drugs that act through competitive inhibition of HIV reverse transcriptase (RT). Thus, the emphasis of current research is on agents with other mechanisms. The possibilities include noncompetitive RT inhibitors, drugs against an entirely different enzyme--HIV proteinase, and measures to enhance immunity, either globally or against HIV specifically.
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PMID:An approach to antiretroviral treatment of HIV disease. New approaches. 754 85

Some retroviruses, including HIV-1, regulate the relative amounts of gag and pol gene products by a translational frameshift mechanism. The consequences of altering the ratios of the Gag and Pol proteins were tested using vaccinia virus expression vectors, in which the gag and pol genes were fused by placing them in the same open reading frame. Immunoblotting of cell lysates indicated that a protein of approximately 160 kDa, the expected translation product of the fused gag-pol gene, was the dominant species detected with HIV-specific antiserum during the first several hours of infection with this recombinant virus. Subsequently, the full-length polyprotein diminished in amount and a series of Gag-related intermediate size proteins appeared. Later in infection, p24 and myristoylated p17 Gag proteins predominated and larger amounts of intracellularly processed reverse transcriptase, integrase, and protease were detected compared to the amounts formed with the wild-type gag-pol gene. Large numbers of budding, immature, and mature retrovirus-like particles were visualized by electron microscopy when the wild-type gag-pol gene was expressed, whereas no particles were detected in cells that expressed the fused gag-pol gene. The block to virus assembly was partially overcome by (i) inhibition of the HIV-1 protease with a peptidomimetic inhibitor, (ii) mutagenesis of the active site of the protease, or (iii) shortening of the Gag-Pol polyprotein by deletion of most of the reverse transcriptase gene. Nevertheless, budding was inefficient and the structures appeared immature and frequently aberrant. These results indicated that overproduction of the full-length Gag-Pol polyprotein and increased intracellular protease activity were both detrimental to viral assembly. Further experiments indicated that intracellular processing of Gag and Gag-Pol polyproteins occurred in the absence of particle formation when myristoylation was prevented.
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PMID:Overexpression of the HIV-1 gag-pol polyprotein results in intracellular activation of HIV-1 protease and inhibition of assembly and budding of virus-like particles. 768 10

Antibody binding to the p 66 and p 15 RNase H regions of HIV-1 reverse transcriptase was compared using a polyclonal rabbit immune serum raised against a synthetic peptide from the RNase H region of reverse transcriptase (aa 511-527) and six monoclonal antibodies binding to discontinuous epitopes in the RNase H region of p 66. The antigens used in Western blot analysis included recombinantly expressed homodimeric p 66 digested with the HIV-1 protease for generation of the p 51 and p 15 polypeptides and two different length RNase H domains expressed as Trp E fusion proteins (aa 410-560 and aa 441-560). The polyclonal rabbit antibody binding to a continuous epitope recognized both the Trp E-fusion proteins and also the polypeptides p 66 and p 15 generated by processing of homodimeric p 66 with the viral protease. Two additional cleavage products with estimated molecular weights of 9 and 11 kDa were also detected. The anti-RNase H MAbs binding to discontinuous epitopes recognized only the RNase H domain of the p 66 polypeptide and the Trp E-RNase H fusion protein when this was expressed together with the C-terminal part of the polymerase domain. The results indicate conformational differences between the RNase H domain of the p 66 subunit and the RNase H p 15 polypeptide.
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PMID:Characterization of HIV-1 reverse transcriptase with antibodies indicates conformational differences between the RNAse H domains of p 66 and p 15. 768 7

A stable cell line encoding the sequences of all the human immunodeficiency virus type 1 proteins, with the exception of the gp160 envelope glycoprotein, was derived from transfection of monkey COS-7 cells. This cell line, referred to as CH-1, produces active viral protease that correctly processes its natural substrates and yields capsid particles. These particles contain reverse transcriptase activity and packaged viral RNA but are noninfectious. The level of expression of viral proteins is not toxic to the cells, yet it is comparable to that observed for chronically infected lymphocytes. These constitutively synthesized viral proteins provide a consistent system for the analysis of potential inhibitors of late viral functions. The lack of gp160 increases the biosafety of this assay system, while it allows the measurement of the effects on the production and release of capsid particles. A human immunodeficiency virus type 1 protease inhibitor was used to confirm the viral polyprotein maturation pathway in this system. Particles from cells treated with this protease inhibitor contain unprocessed p55gag precursor and have the same density as the mature particles. These immature particles contain viral RNA, but reverse transcriptase activity is significantly reduced. This cell line may serve to identify compounds that are able to affect viral assembly and maturation as well as to identify the interactions between the viral and cellular proteins involved in these essential processes.
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PMID:Constitutive production of nonenveloped human immunodeficiency virus type 1 particles by a mammalian cell line and effects of a protease inhibitor on particle maturation. 784 May 83

To date, numerous inhibitors of the human immunodeficiency virus type 1 protease have been reported, but few have been studied extensively in humans, primarily as a consequence of poor oral bioavailability in animal models. L-735,524 represents a class of human immunodeficiency virus type 1 protease inhibitors, termed hydroxyaminopentane amides, that incorporate a basic amine into the hydroxyethylene inhibitor backbone. L-735,524 is a potent inhibitor of virus replication in cell culture and inhibits the protease-mediated cleavage of the viral precursor polyproteins that results in the production of noninfectious progeny viral particles. The compound is effective against viruses resistant to reverse transcriptase inhibitors and is synergistically active when used in combination with reverse transcriptase inhibitors. Most importantly, L-735,524 exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals by using clinically acceptable formulations. Accordingly, the compound was selected for evaluation of safety and pharmacokinetic studies in humans.
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PMID:L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. 817 Oct 40

The bis(monosuccinimide) derivative of p,p'-bis(2-aminoethyl)diphenyl-C60 (compound 1), prepared by the fulleroid route, is active against human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% effective concentration [EC50] averaging approximately 6 microM) in acutely or chronically infected human lymphocytes and is active in vitro against 3'-azido-3'-deoxythymidine-resistant HIV-1 (EC50, approximately 3 microM). The virucidal properties of compound 1 were confirmed by virus inactivation assays. Compound 1 was noncytotoxic up to 100 microM in peripheral blood mononuclear cells and H9, Vero, and CEM cells. In cell-free assays, whereas the fullerene showed comparable activity against HIV-1 reverse transcriptase and DNA polymerase alpha (50% inhibitory concentration of approximately 5 microM), it demonstrated selective activity against HIV-1 protease.
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PMID:Synthesis and virucidal activity of a water-soluble, configurationally stable, derivatized C60 fullerene. 821 89

Upon the binding of a synthetic nonapeptide substrate, the catalytically active dimeric form of HIV proteinase is strongly stabilized against dissociation into inactive subunits. The dissociation of the ternary Michaelis complex into protein monomers is immeasurably low (apparent dissociation constant in the picomolar range), while the dimer-to-monomer equilibrium dissociation constant at pH 4.7 and at ionic strength 1.0 M is 30.4 +/- 1.6 nM. Consequently, the apparent activity of HIV proteinase depends on the order in which the enzyme and the substrate are added to in vitro assays. Substrate-induced stabilization should be carefully considered in designing kinetic studies of all dissociative retroviral enzymes, the proteinase, the integrase, and the reverse transcriptase.
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PMID:Stabilization of HIV proteinase dimer by bound substrate. 833 44

Previous studies have shown that some peptides derived from one of the terminal amino acid segments of the homodimeric HIV-1 protease show moderate inhibition of this enzyme probably by interfering with the "interface" structure formed by the four terminal segments of the dimer. Different peptides, with improved inhibitory potency, were devised by computer modelling, synthesized, and tested. Ac-TVSFNF, the short peptide with the best inhibition so far (IC50 = 80 microM) is identical with the C-terminal part of the gag-pol frame shift protein p6*. This suggests a regulatory function of p6* as a dimerization inhibitor of HIV protease in the virion. Peptides derived from the active site sequence of PR are inactive. The two terminal hexapeptides of reverse transcriptase are also inactive in the HIV-1 PR activity assay.
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PMID:The inhibition of HIV-1 protease by interface peptides. 834 46

A synthetic, symmetry-based inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, A77003, was evaluated for antiviral activity and cytotoxicity in vitro in human peripheral blood lymphocytes or cell lines H9, CEM, and U937. Toxicity and antiviral activity of the HIV-1 protease inhibitor were compared with those of the reverse transcriptase inhibitors zidovudine and 2',3'-dideoxy-2',3'-didehydrothymidine and human recombinant alpha and beta interferons. Production of infectious virus particles, cell-free p24 antigen, and cell-associated viral proteins was reduced 50% by the HIV-1 protease inhibitor at concentrations of 0.12 to 0.26 microM (50% effective concentration [EC50]) in acute infection and 0.2 to 1.7 microM (EC50) in persistent infection. Fluorescence-activated cell sorter analysis of U937 cells persistently infected with HIVIIIB using a monoclonal antibody to HIV also showed a reduction of cell-associated viral protein in A77003-treated cells. Furthermore, toxicity of A77003 assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay was not observed at greater than 100 times the EC50. A77003 was more effective in persistent HIV-1 infection than alpha and beta interferons (1,000 U/ml), while zidovudine and 2',3'-dideoxy-2',3'-didehydrothymidine were not active.
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PMID:Preclinical evaluation of antiviral activity and toxicity of Abbott A77003, an inhibitor of the human immunodeficiency virus type 1 protease. 843 Oct 7

Halogenated gomisin J (a derivative of lignan compound), represented by the bromine derivative 1506 [(6R, 7S, S-biar)-4,9-dibromo-3,10-dihydroxy-1,2,11,12-tetramethoxy-6, 7-dimethyl-5,6,7,8- tetrahydrodibenzo[a,c]cyclo-octene], was found to be a potent inhibitor of the cytopathic effects of human immunodeficiency virus type 1 (HIV-1) on MT-4 human T cells (50% effective dose, 0.1 to 0.5 microM). Gomisin J derivatives were active in preventing p24 production from acutely HIV-1-infected H9 cells. The selective indices (toxic dose/effective dose) of these compounds were as high as > 300 in some systems. 1506 was active against 3'-azido-3'-deoxythymidine-resistant HIV-1 and acted synergistically with AZT and 2',3'-ddC. 1506 inhibited HIV-1 reverse transcriptase (RT) in vitro but not HIV-1 protease. From the time-of-addition experiment, 1506 was found to inhibit the early phase of the HIV life cycle. A 1506-resistant HIV mutant was selected and shown to possess a mutation within the RT-coding region (at position 188 [Tyr to Leu]). The mutant RT expressed in Escherichia coli was resistant to 1506 in the in vitro RT assay. Some of the HIV strains resistant to other nonnucleoside HIV-1 RT inhibitors were also resistant to 1506. Comparison of various gomisin J derivatives with gomisin J showed that iodine, bromine, and chlorine in the fourth and ninth positions increased RT inhibitory activity as well as cytoprotective activity.
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PMID:Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1 reverse transcriptase. 854 Jul 6


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