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)

Recent advances in a new method for the de novo design of enzyme inhibitors are reported. A new set of rules to define the possible nonbonded contacts between protein and ligand is presented. This method was derived from published statistical analyses of nonbonded contacts in crystal packings of organic molecules and has been implemented in the recently described computer program LUDI. Moreover, LUDI can now append a new substituent onto an already existing ligand. Applications are reported for the design of inhibitors of HIV protease and dihydrofolate reductase. The results demonstrate that LUDI is indeed capable of designing new ligands with improved binding when compared to the reference compound.
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PMID:LUDI: rule-based automatic design of new substituents for enzyme inhibitor leads. 129 28

The RNase H domain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase was released from recombinant DHFR-RNase H fusion protein by the action of HIV-1 protease and crystallized as large trigonal prisms that diffract x-rays to at least 2.4-A resolution. The protease cleavage occurred 18 residues away from the Phe440-Tyr441 site reported to be processed during maturation of the reverse transcriptase heterodimer. Mutagenesis of the protease-sensitive region (residues 430-440), which is part of the crystallized domain, indicates that any alteration of the wild-type sequence results in increased proteolysis of the p66 subunit. A model of asymmetric processing in HIV-1 reserve transcriptase which involves partial unfolding of the RNase H domain is proposed based on these results and the recently reported three-dimensional structure of this domain.
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PMID:Proteolytic release and crystallization of the RNase H domain of human immunodeficiency virus type 1 reverse transcriptase. 171 88

A synthetic gene coding for HIV-1 protease (PR) has been constructed and a system for its efficient expression in E. coli has been established: PR is synthesized as a fusion protein with E. coli dihydrofolate reductase under the control of a bacteriophage T7 promoter. The synthetic gene was constructed to enable rapid construction of defined mutants by restriction fragment replacement. A set of mutants has been constructed which may facilitate elucidation of the mechanism of PR self-cleavage from polyprotein precursors. We have demonstrated that the C-terminal residue (Phe99 in the native sequence) of the processing intermediate is absolutely required for subsequent cleavage at the N-terminal cleavage site. The potential structural role of this residue is discussed with reference to the recently published HIV-1 PR structure.
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PMID:High-level expression of self-processed HIV-1 protease in Escherichia coli using a synthetic gene. 266 71

Recombinant and synthetic peptides corresponding to envelope proteins of the human immunodeficiency virus (HIV) were examined for their effects on the activities of lymphocytes from normal donors in vitro. Although lymphocytes cultured with env-gag peptides produced significant amounts of IgG, addition of env-gag peptides to a pokeweed mitogen-induced B-cell activation system resulted in suppression of immunoglobulin synthesis by normal lymphocytes. Recombinant antigens, env-gag and env-80 dihydrofolate reductase (DHFR), produced a substantial proliferative response by peripheral blood mononuclear cells (PBMC) as determined by [3H]thymidine incorporation. PBMC precultured with HIV synthetic peptide env 578-608 also manifested significant proliferative responses as compared to control cultures. CD3+ lymphocytes precultured with recombinant HIV antigens, env-gag and env-80 DHFR, and synthetic HIV peptide, env 487-511, showed moderate but significant proliferative responses. Both recombinant antigens and synthetic peptides also produced a dose-dependent stimulatory effect on proliferation by CD3- lymphocytes. Stimulation of CD3+ and CD3- lymphocyte subpopulations induced by env-gag peptides was specifically inhibited by goat anti-env-gag polyclonal antibodies, demonstrating the specificity of the reaction. These studies demonstrate that recombinant and synthetic peptides of the HIV genome express immunoregulatory T- and B-cell epitopes. Identification of unique HIV epitopes with immunogenic and immunoregulatory activities is necessary for the development of an effective vaccine against HIV infection.
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PMID:Immunoregulatory activities of human immunodeficiency virus (HIV) proteins: effect of HIV recombinant and synthetic peptides on immunoglobulin synthesis and proliferative responses by normal lymphocytes. 304 18

To gain further insight into the genetic variability between different isolates of Pneumocystis carinii of rat and human origin, we sequenced three DNA regions from the mitochondrial rRNA gene, the 5S rRNA gene and the dihydrofolate reductase gene (DHFR) of microorganisms isolated from three different immunosuppressed rat sources and from one HIV + patient with P. carinii pneumonia. Some point mutations and deletions were found among rat isolates in two regions (mitochondrial rRNA gene and 5S rRNA gene). Nucleotide sequence variations in these conserved regions support the hypothesis of the existence of several Pneumocystis strains infecting the same host species.
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PMID:Genetic variability in different Pneumocystis isolates from man and rats. 755 73

Two computational techniques have been developed to explore the orientational and conformational space of a flexible ligand within an enzyme. Both methods use the Genetic Algorithm (GA) to generate conformationally flexible ligands in conjunction with algorithms from the DOCK suite of programs to characterize the receptor site. The methods are applied to three enzyme-ligand complexes: dihydrofolate reductase-methotrexate, thymidylate synthase-phenolpthalein and HIV protease-thioketal haloperidol. Conformations and orientations close to the crystallographically determined structures are obtained, as well as alternative structures with low energy. The potential for the GA method to screen a database of compounds is also examined. A collection of ligands is evaluated simultaneously, rather than docking the ligands individually into the enzyme.
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PMID:Flexible ligand docking using a genetic algorithm. 760 43

A region of the human Ha-ras promoter (-8 to -28) which contains two of the three Sp1 binding sites essential for transcriptional activity forms a sequence specific oligonucleotide-directed pur*pur:pyr triple helix. The relative binding of oligonucleotides containing different substitutions, including an abasic propanediol linker, over three potentially destabilizing C:G interruptions in the otherwise poly G:poly C target was examined. DNase I footprint titrations reveal that substitution of the positively charged abasic propanediol linker results in approximately ten fold greater binding than cytosine substitution which in turn provides greater sequence specific binding than substitution of a guanine in the third strand oligonucleotide over the C:G interruptions. Protein binding assays demonstrate that triplex formation by the linker substituted oligomer (HR21Xap) is less effective in inhibiting Sp1 binding than the cytosine substituted oligomer (HR21ap) both to the target sequence as well as an upstream sequence. As an indication of the effect of linker substitution and targeting consensus Sp1 sites on triplex specificity, the relative ability of the Ha-ras promoter targeted oligonucleotides to interact with non-target Sp1 sequences within the Ha-ras promoter as well as in the DHFR promoter and HIV-1 LTR was also investigated. At concentrations which afford complete DNase I protection of the target sequence, HR21ap does not bind to the non-target sequences while HR21Xap interacts weakly only at a distal site in the DHFR promoter. Also, HR21ap as well as HR21Xap are specific in their inhibition of Sp1 binding. These results suggest that the propanediol linker is able to skip over interruptions in a target sequence thereby stabilizing triplex but, slightly compromises sequence specificity and the ability to inhibit Sp1 binding to the Ha-ras promoter.
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PMID:Effect of abasic linker substitution on triplex formation, Sp1 binding, and specificity in an oligonucleotide targeted to the human Ha-ras promoter. 820 18

The anti-human immunodeficiency virus (anti-HIV) agent 2',3'-didehydro-3'-deoxythymidine (D4T), like other 2',3'-dideoxynucleosides, requires conversion to its 5'-triphosphate to exert its pharmacological effect. Although D4T-triphosphate is unusually potent as an inhibitor of HIV-1 reverse transcriptase, the phosphorylation of the drug at low dose levels is inefficient because of its low affinity as an alternate substrate for the initial phosphorylation enzyme thymidine kinase. Because thymidine kinase is under feedback regulatory control by the physiological deoxynucleoside-5'-triphosphate dTTP, we examined the effect on D4T phosphorylation and thus, potentially, on its antiviral activity, of a variety of agents that lower intracellular dTTP pools. We found that agents that inhibit the de novo pyrimidine biosynthetic pathway have the ability to increase D4T phosphorylation, the most effective being two inhibitors of thymidylate formation, methotrexate and 5-fluoro-2'-deoxyuridine, compounds that block the enzymes dihydrofolate reductase and thymidylate synthetase, respectively. Because HIV itself lacks the capacity to synthesize dTTP and the other deoxynucleoside triphosphates essential for viral replication, combinations of D4T with modulatory agents that deplete host-cell dTTP, unlike conventional anti-HIV drug monotherapy directed solely at viral enzymes, have the ability to inhibit replication of mutant HIV strains as well as of wild-type virus.
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PMID:2',3'-Didehydro-3'-deoxythymidine: regulation of its metabolic activation by modulators of thymidine-5'-triphosphate biosynthesis. 870 Jan 8

Leucine-rich nuclear export signals (NESs) are recognized by the NES receptor exportin 1 and are central to the export of multiple shuttling proteins and RNAs. The export of messenger RNA in vertebrates was, however, thought to occur by a different pathway, because inhibition by injection of a synthetic Rev NES conjugate could not be demonstrated. Here we find that peptide conjugates composed of the NES of either protein kinase A inhibitor protein (PKI) or the HIV-1 Rev protein, when coupled to human serum albumin, are potent inhibitors of mRNA and small nuclear RNA export. These results provide direct evidence that mRNA export in vertebrates depends on interactions between an NES and its cognate NES receptors. PKI NES conjugates are significantly more efficient at inhibiting RNA export than are REV NES conjugates, indicating that different NESs may have different abilities to promote protein and RNA export. Surprisingly, an expected control conjugate containing the mutant Rev NES sequence M10 strongly inhibited the export of intronless dihydrofolate reductase mRNA. Nuclear injection of NES peptide conjugates led to mislocalization to the nucleus of 10-20% of the cytoplasmic Ran GTPase-binding protein (RanBP1) indicating that RanBP1 shuttles between the nucleus and the cytoplasm via an NES pathway. These results demonstrate that in vertebrates the export of mRNA, like that of small nuclear RNA, 5S rRNA, and transport factors such as RanBP1, employs NES-mediated molecular machinery.
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PMID:Inhibition of mRNA export in vertebrate cells by nuclear export signal conjugates. 940 23

Recombinant and synthetic peptides derived from the human immunodeficiency virus type I (HIV-1) genome corresponding to portions of the envelope (env) and internal core protein (gag) were examined for their immunoregulatory effects on the natural killer (NK) cell activity of lymphocytes from healthy donors and from patients with the acquired immunodeficiency syndrome (AIDS). Two recombinant peptides (env-gag and Env 80-DHFR) and three chemically synthesized peptides (env 487-511, env 578-608 and env 647-659) were used. Normal lymphocytes precultured for 24 to 72 hrs. with either env-gag, env 487-511, or env 647-659 at 5 and 50 ng/ml concentrations which significantly stimulated lymphocyte proliferation, produced significant suppression of NK activities. Two control peptides, one derived from the E. coli vector used to clone the HIV env-gag fusion peptide and another, a non-HIV-1 viral antigen (rubeola virus) did not produce any observable effect on NK activity of normal lymphocytes demonstrating the specificity of the reaction. Env-gag peptide also inhibited the NK activities of Percoll-separated, NK-enriched large granular lymphocytes. In target binding assays, lymphocytes precultured with env-gag significantly suppressed the target binding capacity of effector cells and produced significantly lower levels of natural killer cytotoxic factor (NKCF). In kinetic studies, lymphocytes from normal donors preincubated with env-gag for 24 to 72 hrs. produced significant inhibition of their NK activity and an even greater inhibitory effect on NK activities was observed when lymphocytes from AIDS patients were preincubated with HIV peptides. Thus HIV-1 peptides, which we previously demonstrated could regulate B- and T-lymphocyte activities, are also capable of regulating the NK activities of lymphocytes from HIV-1-infected and normal individuals.
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PMID:Inhibition of natural killer cell activities from normal donors and AIDS patients by envelope peptides from human immunodeficiency virus type I. 944 29


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