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)

Furin is a subtilisin-like eukaryotic serine endoprotease which processes proproteins to biologically active proteins and peptides. Also, the envelope proteins of viruses, such as influenza and HIV viruses, need to be processed by furin for infectivity. This enzyme has a consensus substrate specificity for Arg-Xxx-Lys/Arg-Arg at the cleavage site. Two kinds of transition state analog peptides were designed and tested in vitro with furin. The ketomethylene series, psi (COCH2), have Ki's in the submicromolar range; the aminomethyl aminomethyl ketone series, psi(COCH2NH), have Ki's in the nanomolar range. The best inhibitor is Dec-Arg-Val-Lys-Arg-CH2-Ala-Val-Gly-NH2 (2c) with a Ki of 3.4 nM.
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PMID:Synthesis of tight binding inhibitors and their action on the proprotein-processing enzyme furin. 756 36

Vpr is a conserved HIV-1 auxiliary protein that localizes to the nuclear region of cells. Vpr is also present in virions, and it is directed into the assembling virus when coexpressed with Gag. Each of these two localization activities may be important for Vpr function, and we recently identified regions of Vpr that are critical for virion incorporation. In this study we analyzed the Vpr domains involved in subcellular localization. Immunofluorescence staining of transfected cells showed that wild-type Vpr localized exclusively to the nuclear region. Mutations in the N-terminal domain that were designed to disrupt a predicted alpha-helical structure resulted in aberrant localization, while conservative substitutions showed a wild-type pattern. A region in the central portion of the protein also has the potential for helical structure, and mutagenesis of two conserved amino acids in this domain (A59, H71) impaired localization, while substitution of a third (Q65) did not. In contrast, neither the conserved Gly and Cys at positions 75-76 nor the C-terminal basic residues (R87, K95) were necessary for nuclear localization. In addition, two-residue insertions within and between the two putative helices disrupted localization but insertion in the C-terminal region did not. Thus, Vpr's subcellular localization function depends on the two putative helical domains but is independent of the conserved Gly-Cys motif and of specific C-terminal basic residues.
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PMID:Functional analysis of HIV-1 Vpr: identification of determinants essential for subcellular localization. 757 2

The third variable domain (V3 domain) of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 contains a substantial number of positively charged amino acid residues. We previously demonstrated that mutation of basic amino acid residues at position 303, 306, 309, 313, and 325 in the V3 domain of HIV-1 strain NL4-3 resulted in a dramatic elimination of both virus infectivity and syncytium-inducing ability. Mutations of arginine at position 302 to serine (R302S) or lysine at position 320 to glutamine (K320Q) had variable effects on infectivity for a panel of T cell lines tested. These mutations are located on opposite sides of the Gly-Pro-Gly-Arg-Ala sequence in the center of the V3 domain. The R302S and K320Q mutations allowed us to determine if these basic residues are important for virus neutralization by polyanionic compounds. Dextran sulfate and heparin inhibited the cytopathogenicities of both mutants for MT-4 cells, although their 50% antiviral effective doses were slightly higher than those required to achieve complete protection against wild-type HIV-1NL4-3 replication. This result emphasizes that the basic amino acids of Arg302 and Lys320 are not essential for the inhibitory effect of dextran sulfate and heparin on HIV-1 infection.
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PMID:Single basic amino acid substitutions at position 302 or 320 in the V3 domain of HIV type 1 are not sufficient to alter the antiviral activity of dextran sulfate and heparin. 757 13

During replication of human immunodeficiency virus type 1 (HIV-1), proteolytic cleavage of Gag and Gag-Pol precursor proteins into different functional protein subunits is catalyzed by the viral proteinase, and this enzyme is the target of the antiviral proteinase inhibitor, Ro 31-8959. We investigated in vitro which HIV mutants with reduced sensitivity to Ro 31-8959 emerged during proteinase inhibition treatment; from three different HIV-1 strains, comparable progeny virus resistant to proteinase inhibitor were found, whereas the same experimental protocol detected no resistant HIV-2 mutants. Molecular analysis of the mutations underlying resistance revealed a multistep mechanism in which an amino acid exchange was common to all resistant isolates, and in all experiments preceded further exchanges at position 90 (leucine to methionine) and/or at position 54 (isoleucine to valine). For wild-type strains the 90% inhibitory concentrations of Ro 31-8959 were close to 20 nM, whereas HIV-1 mutants with all 3 amino acid exchanges had more than 50-fold increased 90% inhibitory concentrations (above 1000 nM). The primary event (Gly-48 to valine) occurs at the hinge of the flaps of the proteinase, thus hampering entry of the inhibitor to the active center and suggesting steric hindrance. Detailed knowledge of this stereotypic process could open inhibitor design, thus preventing conceivable escape of resistant virus on proteinase inhibitor action.
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PMID:Resistance of HIV type 1 to proteinase inhibitor Ro 31-8959. 757 26

Nevirapine is a highly potent and specific inhibitor of human immunodeficiency virus type 1 (HIV-1) polymerase, but is inactive against HIV-2 and other polymerase. Previous studies demonstrated that residues 176-190 of HIV-1 reverse transcriptase (RT) can confer nevirapine sensitivity to HIV-2 RT. To better characterize the role of this sequence in HIV-1 RT, we have progressively substituted residues 176-190 of HIV-2 RT for those of HIV-1 RT and monitored the impact on the kinetic properties; inhibitory activity of nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[2,3-b:2',3'-e] [1,4]diazepin-6-one), E-BPU (5-ethyl-1-benzyloxymethyl-6-(phenylthio)-uracil), and TIBO-R82150 ((+)-S-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-j k] [1,4]benzodiazepin-2(1H)-thione); and inhibitor-induced fluorescence changes of the mutant enzymes. The study revealed that in addition to Try-181 and Tyr-188, a new amino acid residue (Gly-190) plays an important role in determining susceptibility to nevirapine and E-BPU, but not to TIBO-R82150. These data argue that these non-nucleoside inhibitors fit differently, even though they share a common binding pocket. Nevirapine was seen to exert inhibitory activity by altering the interaction of the enzyme with the template-primer. Kinetic parameters were modulated by the template (DNA versus RNA) as well as by some of the mutations.
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PMID:Amino acid substitutions in HIV-1 reverse transcriptase with corresponding residues from HIV-2. Effect on kinetic constants and inhibition by non-nucleoside analogs. 768 67

A human immunodeficiency virus type 1 (HIV-1) variant with highly reduced susceptibility to Ro 31-8959, an inhibitor of the viral proteinase, has been selected by repeated passage of wild-type virus in CEM cells in the presence of increasing concentrations of the inhibitor. Peptide sequences of the proteinase of selected virus were obtained from proviral DNA. Sequence comparison to wild-type (wt) proteinase demonstrated two amino acid substitutions in the resistant virus, a Gly to Val exchange at position 48 and a Leu to Met exchange at position 90. Furthermore, sequences of intermediate passage virus suggest contributions from positions 12, 36, 57, and 63 in early steps of resistance development. The selected virus showed a ca. 40-fold increase in 50% inhibitory concentration of Ro 31-8959. Growth kinetics of resistant virus were comparable to wild-type virus and the resistant genotype proved to be stable in the absence of inhibitor. Directed mutagenesis of the HIV-1 HXB2 proteinase at positions 48 and 90 suggested that each mutation alone led to a moderate decrease in sensitivity of the recombinant virus to proteinase inhibitor. However, a recombinant virus carrying both mutations in the proteinase gene showed a significant reduction in its sensitivity to Ro 31-8959 thus proving the importance of these exchanges for the resistance phenotype.
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PMID:Characterization of human immunodeficiency virus type 1 mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959. 783 7

The synthetic hydrophobic peptide, Z-D-Phe-L-Phe-Gly, was shown previously to inhibit the infectivity of paramyxoviruses and the fusion of Sendai virus with liposomes. We examined the ability of this peptide to inhibit HIV-1 infectivity in A3.01, Sup-T1, and H9 cells and syncytium formation between these cells and chronically infected H9 cells. Although the peptide inhibited syncytium formation in a dose-dependent manner, its effect on virus infectivity was very limited. Our results suggest that the mechanisms of interaction of the HIV-1 envelope glycoprotein gp120/gp41 with the target cell membrane leading to membrane fusion may be different in cell-cell and virus-cell fusion.
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PMID:Differential effects of a hydrophobic tripeptide on human immunodeficiency virus type 1 (HIV-1)-induced syncytium formation and viral infectivity. 788 68

Mutations in the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins gp120 and gp41, previously shown to confer an enhanced replicative capacity and broadened host range to the ELI1 strain of HIV-1, were analyzed for their biochemical effects on envelope structure and function. The tendency of purified virions to release their extracellular gp120 component, either spontaneously or after interacting with soluble CD4 (CD4-induced shedding) was assessed. A single amino acid substitution in part of the CD4 binding site of gp120 (Gly-427 to Arg) enhanced both spontaneous and CD4-induced shedding of gp120 from virions, while a single change in the fusogenic region of gp41 (Met-7 to Val) affected only CD4-induced shedding. Although each codon change alone conferred increased growth ability, virus with both mutations exhibited the most rapid replication kinetics. In addition, when both of these mutations were present, virions had the highest tendency to shed gp120, both spontaneously and after exposure to soluble CD4. Analysis of CD4 binding to virion-associated gp120 showed that the changes in both gp120 and gp41 contributed to increased binding. These results demonstrated that the increased replicative capacity of the ELI variants in human CD4+ cell lines was associated with altered physical and functional properties of the virion envelope glycoproteins.
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PMID:Increase in soluble CD4 binding to and CD4-induced dissociation of gp120 from virions correlates with infectivity of human immunodeficiency virus type 1. 790 56

The reactivity of monoclonal antibodies (Mabs) raised against a cyclic peptide representing a chimeric V3 loop of HIV-1 gp120 with different peptide analogues was studied with a biosensor system (BIAcore) and by ELISA. In both assays, the Mabs cross-reacted extensively with the V3 regions of different HIV-1 strains and recognized the cyclic form of the peptide immunogen better than its linear form. The highest degree of cross-reactivity was observed with peptides that shared a Lys312 with the chimeric sequence. Dissociation rate constants of ten Mabs measured with the BIAcore with respect to different peptides increased with increasing numbers of substitutions in the flanking regions of the V3 tip sequence Gly Pro Gly Arg. Immobilization of the cyclic peptide on the sensor chip via a thiol group added near the end of the loop structure preserved the conformation of the peptide. In view of the good correlation between the BIAcore and ELISA results, biosensor data should be useful for selecting peptides to be used in diagnostic solid phase assays.
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PMID:Cross-reactivity of monoclonal antibodies to a chimeric V3 peptide of HIV-1 with peptide analogues studied by biosensor technology and ELISA. 798 80

The glycosphingolipid galactosylceramide (GalCer), which binds gp120 with high affinity and specificity, is a potential alternative receptor for human immunodeficiency virus type 1 (HIV-1) in some CD4-negative neural and epithelial human cells, including the human colonic epithelial cell line HT-29. In the present study, we demonstrate that synthetic multibranched peptides derived from the consensus sequence of the HIV-1 V3 loop block HIV-1 infection in HT-29 cells. The most active peptide was an eight-branched multimer of the motif Gly-Pro-Gly-Arg-Ala-Phe which at a concentration of 1.8 microM induced a 50% inhibition of HIV-1 infection in competition experiments. This peptide was not toxic to HT-29 cells, and preincubation with HIV-1 did not affect viral infectivity, indicating that the antiviral activity was not due to a nonspecific virucidal effect. Using a high-performance thin-layer chromatography binding assay, we found that multibranched V3 peptides recognized GalCer and inhibited binding of recombinant gp120 to the glycosphingolipid. In addition, these peptides abolished the binding of an anti-GalCer monoclonal antibody to GalCer on the surface of live HT-29 cells. These data provide additional evidence that the V3 loop is involved in the binding of gp120 to the GalCer receptor and show that multibranched V3 peptides are potent inhibitors of the GalCer-dependent pathway of HIV-1 infection in CD4-negative mucosal epithelial cells.
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PMID:Synthetic multimeric peptides derived from the principal neutralization domain (V3 loop) of human immunodeficiency virus type 1 (HIV-1) gp120 bind to galactosylceramide and block HIV-1 infection in a human CD4-negative mucosal epithelial cell line. 798 25


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