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: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synthetic peptide analog inhibitors of human immunodeficiency virus type 1 (HIV-1) protease were used to study the effects of inhibition of polyprotein processing on the assembly, structure, and infectivity of virions released from a T-cell line chronically infected with HIV-1. Inhibition of proteolytic processing of both Pr55gag and Pr160gag-pol was observed in purified virions from infected T cells after treatment. Protease inhibition was evident by the accumulation of precursors and processing intermediates of Pr55gag and by corresponding decreases in mature protein products. Electron microscopy revealed that the majority of the virion particles released from inhibitor-treated cells after a 24-h treatment had an immature or aberrant capsid morphology. This morphological change correlated with the inhibition of polyprotein processing and a loss of infectivity. The infectivity of virion particles purified from these chronically infected cell cultures was assessed following treatment with the inhibitor for 1 to 3 days. Virions purified from cultures treated with inhibitor for 1 or 2 days demonstrated a 95- to 100-fold reduction in virus titers, and treatment for 3 days resulted in complete loss of detectable infectivity. The fact that virions from treated cultures were unable to establish infection over the 7- to 10-day incubation period in the titration experiments strongly suggests that particles produced by inhibitor-treated cells were unable to reactivate to an infectious form when they were purified away from exogenous protease inhibitor. Thus, a block of HIV-1 protease processing of viral polyproteins by specific inhibitors results in a potent antiviral effect characterized by the production of noninfectious virions with altered protein structures and immature morphologies.
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PMID:Human immunodeficiency virus type 1 protease inhibitors irreversibly block infectivity of purified virions from chronically infected cells. 151 Apr 24

Free energy simulations (slow-change method) have been used to estimate quantitatively the ratio of the binding constants of (S) and (R) isomers of a novel HIV protease inhibitor, JG365. As a starting geometry, we used the X-ray crystallographic structure of a complex of HIV protease and JG365 provided by A. Wlodawer. According to our results the (S) configuration, i.e. the form previously identified experimentally, binds considerably more tightly to the protease (delta delta G degrees = 2.9 kcal/mol). When the (S) inhibitor is bound, there is a very strong preference for protonation of the Asp125 (rather than the Asp25) residue of the protease. This study is the first to apply a new method for quantitatively assessing the precision of free energies calculated by the slow-change method.
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PMID:Application of free energy simulations to the binding of a transition-state-analogue inhibitor to HIV protease. 163 Oct 42

Recently, the novel cyclooctylpyranone HIV protease inhibitor 1 was identified in our labs, and an X-ray structure of this inhibitor complexed with HIV-2 protease was obtained. This crystal structure was used to develop two strategies for creating derivatives of 1 with enhanced enzyme inhibitory activity. The first strategy, substitution on the cyclooctyl ring, met with limited success, but provided some interesting information about the conformationally-flexible cycloocytyl ring on the inhibitors. The second strategy, substitution at the meta position of the aryl ring, was far more successful and generated compounds, such as the carboxamide derivatives 41 (Ki = 3.0 +/- 0.4 nM) and 36 (Ki = 4.0 +/- 0.8 nM), which were significantly more active than the corresponding unsubstituted cycloocytlpyranone 2 (Ki = 11.7 +/- 4.7 nM). An X-ray crystal structure of 36 complexed with HIV-1 protease indicated the increase in binding affinity is most likely due to the additional interactions between the amide substituent and the S3 region of the protease.
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PMID:Structure-based design of nonpeptidic HIV protease inhibitors from a cyclooctylpyranone lead structure. 747 73

Human immunodeficiency virus type 1 (HIV-1) protease inhibitor-resistant variants, isolated on passage of HIV-1HXB2 in MT-4 cells with five different protease inhibitors, have been examined for cross-resistance to five inhibitors. The protease inhibitors studied were Ro 31-8959, A-77003, XM323, L-735,524, and VX-478. Resistant variants with two to four mutations within their protease sequence and 9- to 40-fold-decreased susceptibility were selected for all five inhibitors within six to eight passes in cell culture. Passage of a zidovudine-resistant mutant in Ro 31-8959 generated a dual reverse transcriptase- and protease-resistant virus. Variants were cloned directly into a modified pHXB2-D infectious clone for cross-resistance analysis. Although the resistant variants selected possessed different combinations of protease mutations for each inhibitor, many showed cross-resistance to the other inhibitors, and one showed cross-resistance to all five inhibitors. Interestingly, some mutants showed increased susceptibility to some inhibitors. Further HIV passage studies in the combined presence of two protease inhibitors demonstrated that in vitro it was possible to delay significantly selection of mutations producing resistance to one or both inhibitors. These studies indicate that there may be some rationale for combining different protease inhibitors as well as protease and reverse transcriptase inhibitors in HIV combination therapy.
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PMID:Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. 748 5

We recently purified the calcium-independent processing protease named viral envelope glycoprotein maturase (VEM), that converts human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein precursor gp160 to gp120 and gp41, from the human CD4+ T cell line, Molt-4 clone 8 [Kido, H., Kamoshita, K., Fukutomi, A., and Katunuma, N. (1993) J. Biol. Chem. 268, 13406-13413]. In this report, we deal with the inhibitor specificity and calcium requirement for intracellular gp160 processing in cultured HeLa cells and human CD4+ lymphocytes. Processing of gp160 in these cells infected with recombinant vaccinia virus encoding the gp160 gene was not affected by intracellular calcium depletion induced by the calcium ionophore A23187 and EGTA or by intracellular calcium administration. Processing of gp160 by the purified VEM in vitro was not inhibited by EDTA, EGTA, or the metallo-protease inhibitor phosphoramidon, but was specifically inhibited by a substrate analog, decanoyl-RVKR-chloromethylketone, and the trypsin-type protease inhibitors aprotinin, HI-30, and diisopropyl fluorophosphate (DFP). It was also inhibited by E-64 and thiol reagents. But intracellular gp160 processing was inhibited only by permeable, low molecular mass inhibitors of VEM, such as DFP, E-64, and thiol reagents. Syncytium formation induced by cell surface gp120 was also inhibited by permeable inhibitors of VEM. Taken together, our results indicate that calcium ions may not be essential for intracellular gp160 processing and so HIV-1 gp160 induced by recombinant vaccinia virus may be processed mainly by a protease(s) that does not require calcium ions, such as VEM in these cells.
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PMID:Calcium requirement and inhibitor spectrum for intracellular HIV type 1 gp160 processing in cultured HeLa cells and CD4+ lymphocytes: similarity to those of viral envelope glycoprotein maturase. 749 Feb 67

Combination regimens against human immunodeficiency virus type 1 (HIV-1) were studied in granulocyte-macrophage colony-stimulating factor (GM-CSF)-stimulated monocyte/macrophage cultures. Regimens included those that inhibited the same target (reverse transcriptase) or multiple targets. Treatment conditions assessed efficacy during prophylaxis and ongoing infection. Drugs included zidovudine, didanosine, nevirapine, foscarnet, pyridinone, the protease inhibitor RO31-8959 (also known as saquinavir), interferon-alpha A, the Tat inhibitor RO24-7429, and N-butyl-deoxynojirimycin. Two-, three-, and four-drug combinations were tested. Drugs were tested at individually inhibitory concentrations of IC99, IC95, IC75, and IC50. All prophylactic regimens prevented HIV-1 replication at IC99. As drug concentrations were reduced, differences among the regimens became apparent. Regimens that acted at both single and multiple targets were effective in prophylactic settings and less so in acute infection. In ongoing infections, only modest reductions in viral replication were seen, even at IC99.
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PMID:Inhibition of human immunodeficiency virus type 1 replication in cytokine-stimulated monocytes/macrophages by combination therapy. 752 25

Delavirdine (bisheteroarylpiperazine, U-90152), a nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1), was evaluated in a two-drug combination with recombinant human interferon-alpha (IFN-alpha) or the peptidomimetic protease inhibitor U-75875 against HIV-1 replication in vitro. Viral growth was assayed in a CD4+ T cell line (H9) infected with HIVIIIB and in human peripheral blood mononuclear cells infected with the clinical isolate HIVJRCSF. Drug synergy, estimated by the combination index method and the method of Pritchard and Shipman, was observed when delavirdine was combined with U-75875 or IFN-alpha over a range of drug concentrations (delavirdine: 0.001, 0.003, 0.01, 0.03 microM; U-75875: 0.01, 0.03, 0.1, 0.3, 1.0 microM; IFN-alpha: 2, 6, 17, and 50 or 10, 30, 100, and 300 IU/mL). The combinations showed no detectable drug antagonism or cytotoxicity. These in vitro synergy data support the potential use of delavirdine with either a protease inhibitor or IFN-alpha in patients with AIDS.
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PMID:In vitro inhibition of human immunodeficiency virus type 1 by a combination of delavirdine (U-90152) with protease inhibitor U-75875 or interferon-alpha. 752 53

Tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives were shown to specifically block human immunodeficiency virus type 1 (HIV-1) replication through a unique interaction with the HIV-1 reverse transcriptase (RT). Through further modification of the lead compounds and structure-activity relationship analysis several new TIBO derivatives that show high potency, selectivity, and specificity against HIV-1 have been obtained. A new TIBO derivative, R86183, inhibits the replication of HIV-1, but not HIV-2, in a variety of CD4+ T-cell lines and peripheral blood lymphocytes, at a concentration of 0.3 to 30 nM, which is at least 4 orders of magnitude lower than the 50% cytotoxic concentration. Whereas an HIV-1 strain containing the Leu-100-->Ile mutation in the RT gene is about 400-fold less susceptible, R86183 still inhibits the replication of an HIV-1 strain containing the Tyr-181-->Cys RT mutation by 50% at a concentration of 130 nM. R86183 inhibits the poly(C).oligo(dG)12-18-directed HIV-1 RT reaction by 50% at a concentration of 57 nM. The antiviral activity of 22 TIBO derivatives in cell culture correlated well with their activity against HIV-1 RT. No such correlation was found for their cytotoxicity. The combination of R86183 with either zidovudine or didanosine resulted in a synergistic inhibition of HIV-1 (strain IIIB) replication. Combination of R86183 with the protease inhibitor Ro31-8959 was found to be additive. Also described is a dilution protocol circumventing overestimation and underestimation of antiviral activity due to adherence to plastic surfaces.
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PMID:New tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione derivatives are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2',3'-dideoxynucleoside analogs. 753 37

There are already reports, from clinical trials with human immunodeficiency virus type 1 protease inhibitors, of the emergence of drug-resistant mutants which have one or more point mutations in their protease genes. To examine roles of individual and multiple amino acid substitutions in terms of altered enzyme and virus drug sensitivities, we have produced matched vectors for bacterial expression and virus production. Both vectors accept the same restriction enzyme fragment, produced by PCR or PCR-mutagenesis of the protease gene, allowing parallel expression of mutant enzymes in Escherichia coli and in recombinant viruses. The utility of this vector system was demonstrated by using protease variants glycine to valine at amino acid 48 (G48V) and leucine to methionine at amino acid 90 (L90M) identified after passage of HIV-1 in the Roche phase II clinical trial protease inhibitor Ro 31-8959 (H. Jacobsen, K. Yasargil, D. L. Winslow, J. C. Craig, A. Krohn, I. B. Duncan, and J. Mous, Virology 206:527, 1995). G48V, L90M, and G48V/L90M exhibited successively less processing in vitro than the wild-type enzyme, and the purified enzymes were 220-, 20-, and 720-fold, respectively, less sensitive to Ro 31-8959. The reduced enzyme sensitivity correlated directly with the sensitivities of the matched recombinant viruses, in that individual mutations L90M and G48V conferred 2-fold and 4- to 6-fold increases in 50% inhibitory concentration, respectively, whereas G48V/L90M was 8 to 10 times less sensitive to Ro 31-8959. A proviral vector with the entire protease gene deleted was constructed for use as an in vivo recombination target for an overlapping protease PCR fragment, generating wild-type infectious virus. Finally, direct ligation of restriction fragments, generated from random PCR mutagenesis, into the proviral vector should provide a library of protease mutations that allow extremely rapid selection of highly resistant viral variants.
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PMID:Analysis of resistance to human immunodeficiency virus type 1 protease inhibitors by using matched bacterial expression and proviral infection vectors. 763 88

Synthetic peptide mimetic inhibitors of HIV-1 protease effectively block spread of infectious virus in acutely infected T-cells. These compounds also inhibit production of infectious virions from chronically infected T-cell lines. In order to determine the potential for drug interaction effects on antiviral activity, an HIV-1 protease inhibitor (SK&F 108922) and AZT were studied in three different in vitro models of HIV-1 infection of T-cell lines, specifically, (1) acutely infected cells infected at low multiplicity, (2) HIV-1 chronically-infected cells and (3) co-cultivations of chronically infected with non-infected cells. Upon co-treatment, these compounds demonstrated synergy in Molt4 or H9 cells acutely infected with HIV-1 strain IIIB. Either compound alone was a potent inhibitor of HIV-1 in co-cultivations of uninfected and chronically infected cells. In combination treatments of co-cultures, SK&F 108922 demonstrated strong synergy with AZT. Treatment of H9/IIIB chronically infected cells demonstrated no inhibitory effect by AZT treatment (EC50 = > 100 microM) whereas SK&F 108922 was inhibitory (EC50 = 3 microM). Upon co-treatment of H9/IIIB chronically infected cultures with both compounds, the antiviral activity was similar to that of the protease inhibitor alone suggesting no drug interaction. In the co-cultivation experiments, AZT's antiviral effect was most likely due to blocking spread of acute infection to uninfected cells in the culture. No antagonistic effects were observed with AZT and SK&F 108922 co-treatments. These results clearly demonstrate that an HIV-1 protease inhibitor can exert a potent antiviral effect on chronically infected T-cells in contrast to AZT and is capable of potent synergy with AZT in acute and co-culture in vitro infection models.
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PMID:Synergistic drug interactions of an HIV-1 protease inhibitor with AZT in different in vitro models of HIV-1 infection. 769 16


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