Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 11-kD protease (PR) encoded by the human immunodeficiency virus 1 (HIV-1) is essential for the correct processing of viral polyproteins and the maturation of infectious virus, and is therefore a target for the design of selective acquired immunodeficiency syndrome (AIDS) therapeutics. To facilitate the identification of novel inhibitors of HIV-1 PR, as well as to permit detailed studies on the enzymology and inhibition of this enzyme, a continuous assay for its activity was developed that was based on intramolecular fluorescence resonance energy transfer (RET). The assay used the quenched fluorogenic substrate 4-(4-dimethylaminophenylazo)benzoic acid (DABCYL)--Ser Gln Asn Tyr Pro Ile Val Gln--5-[(2-aminoethyl)amino]naphthalene-1 sulfonic acid (EDANS), whose peptide sequence is derived from a natural processing site for HIV-1 PR. Incubation of recombinant HIV-1 PR with the fluorogenic substrate resulted in specific cleavage at the Tyr-Pro bond and a time-dependent increase in fluorescence intensity that was linearly related to the extent of substrate hydrolysis. An internally quenched fluorogenic substrate was also designed that was selectively cleaved by the related PR from avian myeloblastosis virus (AMV). The fluorescence quantum yields of the HIV-1 PR and AMV PR substrates in the RET assay increased by 40.0- and 34.4-fold, respectively, per mole of substrate cleaved. Because of its simplicity, rapidity, and precision in the determination of reaction rates required for kinetic analysis, this method offers many advantages over the commonly used high-performance liquid chromatography- or electrophoresis-based assays for peptide substrate hydrolysis by retroviral PRs.
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PMID:Novel fluorogenic substrates for assaying retroviral proteases by resonance energy transfer. 210 61

Capillary electrophoresis with laser-induced fluorescent detection, a one-dimensional version of the well-established planar analytical method of polyacrylamide gel electrophoresis, has been proven to be a powerful new microanalytical method for profiling complex carbohydrates. In this paper a comparison is presented between the planar high concentration polyacrylamide gel electrophoresis method and capillary electrophoresis of different carbohydrates with respect to performance and efficiency. N-Linked oligosaccharides were released from several glycoproteins, including fetuin, human immunodeficiency virus (HIV) envelope recombinant glycoprotein (GP-120), alpha 1-acid glycoprotein and ribonuclease B, using recombinant peptide-N-glycosidase F (PNGase F). Both separation methods involve labeling of the released carbohydrates at the reducing end with the fluorescent dye, disodium 8-amino-1,3,6-naphthalene trisulfonate (ANTS). Fluorophore labeling was followed by separation of the labeled oligosaccharides either by high concentration polyacrylamide gel electrophoresis or capillary electrophoresis.
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PMID:Capillary and slab gel electrophoresis profiling of oligosaccharides. 749 47

The National Cancer Institute is pursuing preclinical development of michellamine B (MB), a novel dimeric polyhydroxylated naphthalene-tetrahydroisoquinoline alkaloid isolated from Ancistrocladus abbreviatus, as an anti-human immunodeficiency virus (HIV) agent. MB protects human lymphoid cells from the cytopathic effects of both HIV-1 and HIV-2 in vitro. A specific, sensitive, and convenient method for assaying the compound in biological fluids has been developed. Samples were prepared for analysis by initial treatment with dilute trichloroacetic acid followed by thorough mixing with a solution of the internal standard (alpha-naphthoflavone) in acetonitrile to denature macromolecules. The supernatant afforded by centrifugation, upon dilution with the aqueous component of the liquid chromatographic eluent, was loaded onto a 4-microns Nova-Pak phenyl column (3.9 mm x 15 cm). Chromatography was performed at ambient temperature using an isocratic mobile phase composed of 10 mM octyl sodium sulfate and 15 microM tetrabutylammonium hydrogen sulfate in acetonitrile/0.05 M ammonium formate buffer, pH 4.0 (46/54, v/v), at a flow rate of 0.6 ml/min. The intense native fluorescence of MB, which exhibited excitation and emission maxima in the mobile phase at 232 and 393 nm, respectively, provided a highly sensitive and selective means of detection. Mean values of the retention times for the drug and internal standard determined over 11 months were 10.71 +/- 0.53 and 13.14 +/- 0.52 min, respectively (SD, n = 52). Employing a sample volume of 50 microliters, the lowest concentration of MB included in the standard curves of mouse, dog, and human plasma, 10 ng/ml (11.4 nM), was quantified with coefficients of variation less than 10%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Determination of michellamine B in biological fluids by high-performance liquid chromatography with fluorescence detection. 813 66

In an attempt to find compounds capable of inhibiting the binding and infection by human immunodeficiency virus type 1 (HIV-1) in neural cells, we studied the effect of benzopurpurin and related compounds on the binding of gp120 to galactosyl ceramide (GalCer) and sulfatide. In this report, we show that the binding of gp120 to GalCer and sulfatide is inhibited by benzopurpurin and related compounds. These compounds also inhibit the binding and entry of HIV-1 to neural cell line, SK-N-MC. Binding studies indicate that benzopurpurin and related compounds bind to gp120. Studies involving related compounds indicate that the minimal structure required for the inhibition is two naphthalene rings with amine or sulfonic acids attached to a central biphenyl molecule by an azo group. This approach will be useful for screening of potential anti-HIV compounds.
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PMID:Benzopurpurin and related compounds inhibit the binding of gp120 to galactosyl ceramide/sulfatide and infection of human immunodeficiency virus. 817 24

A series of novel distamycin-related polyanionic compounds were compared for their anti-HIV activity. Several were highly potent inhibitors of HIV virus-induced cell killing and viral replication of a wide variety of laboratory isolates, as well as a monocytotropic virus and a clinical isolate in human peripheral blood lymphocytes. These compounds are structurally different from other sulfonic acid containing compounds reported to be potent inhibitors of the human immunodeficiency virus (HIV) in two respects: (1) they are structurally related to the non-toxic minor groove DNA binder distamycin; and (2) a number of them contain the aromatic phosphonic acid group. The compounds that were evaluated can be categorized into monomeric or dimeric ureido structural classes incorporating the bisamido-N-methylpyrrolenaphthalene-sulfonic acid group, with differences in the number and position of the sulfonic acids on the naphthalene rings. Broader structure-activity studies were made possible through the synthesis and evaluation of the compounds containing only a single N-methylpyrrole unit, those incorporating the N-methylpyrazole structure, and compounds having the isosteric phosphonic acid group substituted for the sulfonic acid group. One of the most potent of the inhibitors was 2,2'[4,4'[[aminocarbonyl]amino]bis[N,4'-di[pyrrole-2-carboxamide- 1,1'-dimethyl]]-4,6,8 naphthalenetrisulfonic acid] hexasodium salt, NSC 651015. This compound, the phosphonic acid analog NSC 662162, and the monomeric compound NSC 651018 were studied to determine the mechanism of their inhibitory activity. Mechanistic studies revealed that inhibition was due to the disruption of virus attachment to CD(4+)-susceptible cells and a further restraint on fusion of virus and cell membranes. The relative tolerance of these compounds in mice suggests that sufficient antiviral concentrations could be reached in vivo and thus may prove valuable in the treatment of AIDS patients.
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PMID:Novel sulfonated and phosphonated analogs of distamycin which inhibit the replication of HIV. 854 Jul 54

PIC 024-4 and PRO 2000 are naphthalene sulfonate polymers that bind to CD4 with nanomolar affinity and block binding of gp120. Both have activity against human immunodeficiency virus type 1 in H9 cells, peripheral blood mononuclear cells, and primary monocyte/macrophages, are synergistic with zidovudine, and do not inhibit tetanus toxoid-stimulated T-cell proliferation at anti-human immunodeficiency virus type 1 concentrations.
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PMID:Naphthalene sulfonate polymers with CD4-blocking and anti-human immunodeficiency virus type 1 activities. 878 13

Using the water-soluble naphthalene carrier of singlet oxygen NDPO2, we have shown that pure singlet oxygen is able to inactivate enveloped viruses (human immunodeficiency virus type 1, herpes simplex virus type 1, cytomegalovirus, vesicular stomatitis virus), but has no effect on non-enveloped viruses (adenovirus and poliovirus 1). These results are related to the experiments on photoinactivation of viruses by hydrophobic photosensitizers (merocyanine 540, hypericin, phthalocyanines, hematoporphyrin and benzoporphyrin derivatives) and they strengthen the hypothesis that singlet oxygen plays a predominant role in this process.
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PMID:Virucidal activity of pure singlet oxygen generated by thermolysis of a water-soluble naphthalene endoperoxide. 898 9

The human immunodeficiency virus type 1 (HIV-1) gp41 plays an important role in membrane fusion between viruses and target cells. The gp41 ectodomain contains two heptad repeat regions adjacent to the N and C-termini. Peptides derived from these two regions, designated N and C-peptides, are potent inhibitors of HIV-1 infection and can interact with each other to form a six-stranded coiled-coil, representing the fusogenic core structure of gp41. A monoclonal antibody was generated, designated NC-1, which specifically binds to the complex formed by the N and C-peptides, but not to the individual peptides. An enzyme linked immunosorbent assay (ELISA) was developed using NC-1 for detecting complex formed by N and C-peptides and for screening of organic compounds for antiviral agents that may interfere with complex formation and inhibit HIV-1 infection. Single point mutations in the C-peptides abolish the complex formation also eliminate their anti-HIV-1 activity. A phenylazo-naphthalene sulfonic acid derivative, designated ADS-J1, was found to inhibit both formation of NC-1 detectable complex and HIV-1-mediated membrane fusion, suggesting that the described ELISA is applicable to rapid screening of libraries of organic compounds for HIV-1 inhibitors targeted to the HIV-1 gp41 core structure.
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PMID:A screening assay for antiviral compounds targeted to the HIV-1 gp41 core structure using a conformation-specific monoclonal antibody. 1040 80

A series of thiazolothiazepines were prepared and tested against purified human immunodeficiency virus type-1 integrase (HIV-1 IN) and viral replication. Structure-activity studies reveal that the compounds possessing the pentatomic moiety SC(O)CNC(O) with two carbonyl groups are in general more potent against purified IN than those containing only one carbonyl group. Substitution with electron-donating or -withdrawing groups did not enhance nor abolish potency against purified IN. By contrast, compounds with a naphthalene ring system showed enhanced potency, suggesting that a hydrophobic pocket in the IN active site might accommodate an aromatic system rather than a halogen. The position of sulfur in the thiazole ring appears important for potency against IN, as its replacement with an oxygen or carbon abolished activity. Further extension of the thiazole ring diminished potency. Compounds 1, 19, and 20 showed antiviral activity and inhibited IN within similar concentrations. These compounds inhibited IN when Mn(2+) or Mg(2+) was used as cofactor. None of these compounds showed detectable activities against HIV-1 reverse transcriptase, protease, virus attachment, or nucleocapsid protein zinc fingers. Therefore, thiazolothiazepines are potentially important lead compounds for development as inhibitors of IN and HIV replication.
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PMID:Thiazolothiazepine inhibitors of HIV-1 integrase. 1046 20

Thiazolothiazepines are among the smallest and most constrained inhibitors of human immunodeficiency virus type-1 integrase (HIV-1 IN) inhibitors (J. Med. Chem. 1999, 42, 3334). Previously, we identified two thiazolothiazepines lead IN inhibitors with antiviral activity in cell-based assays. Structural optimization of these molecules necessitated the design of easily synthesizable analogs. In order to design similar molecules with least number of substituent, herein we report the synthesis of 10 novel analogs. One of the new compounds (1) exhibited similar potency as the reference compounds, confirming that a thiazepinedione fused to a naphthalene ring system is the best combination for the molecule to accommodate into the IN active site. Thus, the replacement of sulfur in the thiazole ring with an oxygen does not seem considerably affect potency. On the other hand, the introduction of an extra methyl group at position 1 of the polycyclic system or the shift from a thiazepine to an oxazepine skeleton decreased potency. In order to understand their mode of interactions with IN active site, we docked all the compounds onto the previously reported X-ray crystal structure of IN. We observed that compounds 7-9 occupied an area close to D64 and Mg(2+) and surrounded by amino acid residues K159, K156, N155, E152, D116, H67, and T66. The oxygen atom of the oxazolo ring of 7 and 8 could chelate Mg(2+). These results indicate that the new analogs potentially interact with the highly conserved residues important for IN catalytic activities.
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PMID:Synthesis of novel thiazolothiazepine based HIV-1 integrase inhibitors. 1526 96


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