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:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The alpha-glucosidase inhibitor N-butyldeoxynojirimycin (NB-DNJ) is an inhibitor of human immunodeficiency virus (HIV) replication and HIV-induced syncytium formation in vitro. Although NB-DNJ appears to inhibit HIV entry at the level of post-CD4 binding (P.B. Fischer, M. Collin, G.B. Karlsson, W. James, T.D. Butters, S.J. Davis, S. Gordon, R.A. Dwek, and F.M. Platt, J. Virol. 69:5791-5797, 1995), the exact mechanism of action remains to be established. In this study we have examined the effect of NB-DNJ on the structure of recombinant gp120 (rgpl20), expressed in CHO cells, by using a panel of 40 monoclonal antibodies. The levels of binding of antibodies to rgp120 produced in the presence [rgpl20(+)] and absence [rgpl20(-)] of NB-DNJ were compared by enzyme-linked immunosorbent assay and surface plasmon resonance (BIAcore; Pharmacia). The results showed an increase in the binding to rgp120(+) of antibodies directed against the C1 and C2 regions and a decrease in the binding of antibodies directed against the V1/V2 loops compared with antibody binding to rgpl20(-). A decrease in the binding to rgpl20(+) of antibodies directed against discontinuous epitopes was also observed. No differences were seen in the binding of antibodies directed against the crown of the V3 loop and the C4 region of gp120. Treatment of rgpl20 with alpha-glucosidases I and II had no effect on the differential binding observed, whereas treatment with sialidase abolished the differences seen in the binding of antibodies directed against the C1 and C2 regions of gp120. In addition to these findings, rgpl20(+) showed increased sensitivity to proteases released by CHO cells during expression, as well as to exogenous thrombin. Taken together, the data presented in this paper suggest that production of gp120 in the presence of NB-DNJ affects the conformation of the Vl/V2 loops of gpl20, as well as the overall charge of the C1 and C2 regions. These effects may play a role in the previously described NB-DNJ-mediated inhibition of HIV entry at the level of post-CD4 binding.
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PMID:N-butyldeoxynojirimycin-mediated inhibition of human immunodeficiency virus entry correlates with changes in antibody recognition of the V1/V2 region of gp120. 879 61

The alpha-glucosidase inhibitor N-butyldeoxynojirimycin (NB-DNJ) is an inhibitor of human immunodeficiency virus (HIV) replication and HIV-induced syncytium formation in vitro. Although an NB-DNJ-mediated change in viral envelope N-glycan composition inhibits HIV entry at the level of post-CD4 binding, the exact mechanism of inhibition remains to be established. In this study we have examined the effects of NB-DNJ on virion envelope composition and CD4-induced gp120 shedding and gp41 exposure. Virion composition analysis revealed an NB-DNJ-mediated reduction of 15% in overall virion envelope glycoprotein content and a reduction of 26% in the proteolytic maturation of virion gp160. Taken together, these two effects resulted in a reduction of approximately 40% in virion gp120 content. CD4-induced shedding of gp120 from the surfaces of envelope-transfected Cos cells was undetectable when gp120 was expressed in the presence of NB-DNJ. Similarly, the shedding of virion-associated gp120 was reduced 7.4-fold. CD4-induced exposure of cryptic gp41 epitopes on the surfaces of HIV-expressing ACH-2 cells was also greatly impaired, and the exposure of virion-associated gp41 epitopes was reduced 4.0-fold. Finally, CD4-induced increases in the binding of antibodies to the V3 loop of ACH-2-cell-expressed envelope glycoproteins were reduced 25-fold when the glycoproteins were expressed in the presence of NB-DNJ. These results suggest that the NB-DNJ-mediated retention of glycosylated N-glycans inhibits HIV entry by a combined effect of a reduction in virion gp120 content and a qualitative defect within the remaining gp120, preventing it from undergoing conformational changes after CD4 binding.
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PMID:N-butyldeoxynojirimycin-mediated inhibition of human immunodeficiency virus entry correlates with impaired gp120 shedding and gp41 exposure. 879 62

N-Linked oligosaccharides play many roles in the fate and functions of glycoproteins. One function is to assist in the folding of proteins by mediating interactions of the lectin-like chaperone proteins calnexin and calreticulin with nascent glycoproteins. These interactions can be prevented by inhibitors of the alpha-glucosidases and this causes some proteins to be misfolded and retained within the endoplasmic reticulum. In human immunodeficiency virus (HIV) and hepatitis B virus (HBV) the misfolding of key viral envelope glycoproteins interferes with the viral life cycle. It has been demonstrated in an animal model of chronic HBV that glucosidase inhibitors can alter glycosylation and have anti-viral activity. As the mechanism of action of alpha-glucosidase inhibitors is the induction of misfolded or otherwise defective viral glycoproteins, such inhibitors may be useful therapeutics for many viruses, especially those which bud from the endoplasmic reticulum (where protein folding takes place). For example bovine viral diarrhea virus, a pestivirus akin to hepatitis C virus, is also extremely sensitive to glucosidase inhibition.
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PMID:Alpha-glucosidase inhibitors as potential broad based anti-viral agents. 967 87

A variety of milk proteins including lactoferrin, angiogenin-1, alpha-lactalbumin, beta-lactoglobulin, lactoperoxidase, casein and the novel whey proteins lactogenin and glycolactin were tested for inhibitory activity toward human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT), alpha-glucosidase, beta-glucosidase and beta-glucuronidase. Lactoferrin exerted the most potent inhibitory action with an IC50 of about 6 microM. Lactoperoxidase, lactogenin, angiogenin-1 and glycolactin inhibited HIV-1 RT activity with decreasing potencies. Beta-lactoglobulin, alpha-lactalbumin and casein displayed little or no inhibitory effect. Succinylation with succinic anhydride augmented the inhibitory effect of glycolactin, beta-lactoglobulin, alpha-lactalbumin, casein and human lactoferrin. The inhibitory effect of the various milk proteins on the activities of alpha-glucosidase, beta-glucosidase and beta-glucuronidase was meager. Succinylation tended to increase the alpha-glucosidase-inhibitory effect of milk proteins but neither their beta-glucosidase-inhibitory nor beta-glucuronidase-inhibitory effect was affected.
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PMID:First demonstration of an inhibitory activity of milk proteins against human immunodeficiency virus-1 reverse transcriptase and the effect of succinylation. 1110 90

Evidence is presented for the existence of multiple proteins with antifungal and antiviral potency in cowpea seeds. The two proteins, designated alpha- and beta-antifungal proteins in accordance with their order of elution from the CM-Sepharose column, were capable of inhibiting human immunodeficiency virus (HIV) reverse transcriptase and one of the glycohydrolases associated with HIV infection, alpha-glucosidase, but beta-glucuronidase was not repressed. The ability of the proteins in retarding mycelial growth of a variety of fungi was also demonstrated with alpha-antifungal protein being more potent in most of the cases. Beta-antifungal protein was more active in only one instance. Both antifungal proteins had low cell-free translation-inhibitory activity. The proteins were adsorbed on Affi-gel blue gel-and CM-Sepharose but could be separated from one another during chromatography on the latter medium by means of a linear NaCl concentration gradient. Different molecular weights were exhibited by the proteins, being 28 kDa and 12 kDa respectively for alpha- and beta- antifungal proteins. Alpha-antifungal protein was characterized by an N-terminal sequence showing close resemblance to sequences of chitinases. Beta-antifungal protein exhibited an N-terminal sequence hitherto unknown in the literature.
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PMID:Structurally dissimilar proteins with antiviral and antifungal potency from cowpea (Vigna unguiculata) seeds. 1119 27

A protein designated hypogin, with a prominent suppressive action on the growth of the fungi Mycosphaerella arachidicola, Fusarium oxysporum and Coprinus comatus, was isolated from seeds of the peanut Arachis hypogaea. The protein inhibited human immunodeficiency virus (HIV) reverse transcriptase and enzymes associated with HIV infection including alpha-glucosidase and beta-glucosidase. The proliferative response of mouse splenocytes was attenuated in the presence of the protein. The protein exhibited a molecular mass of 7.2 kDa in tricine gel electrophoresis and gel filtration on Superdex 75 and an N-terminal sequence resembling peanut allergen Ara H1. The isolation procedure involved affinity chromatography on Affi-gel blue gel and ion-exchange chromatography on CM-Sepharose. The protein was adsorbed in both chromatographic media.
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PMID:Hypogin, a novel antifungal peptide from peanuts with sequence similarity to peanut allergen. 1132 90

From the roots of the Chinese medicinal herb Pseudostellaria heterophylla a single-chained lectin with a molecular weight of 36 kDa and high hemagglutinating activity was isolated. The lectin was adsorbed on DEAE-cellulose in 10 mM Tris-HCI buffer (pH 7.4) and was eluted by the same buffer containing 50 mM NaCl. It was adsorbed on SP-Sepharose in 10mM NH4OAc (pH 4.5) and eluted by approximately 0.5 M NaCl in the same buffer. The hemagglutinating activity of the lectin could not be inhibited by a large variety of monosaccharides, but was largely abrogated by exposure to 0.05 M HCl, 0.05M NaOH or 80 degrees C. However, about 50% of the activity remained after exposure to 0.025M NaOH or 40 degrees C. Despite possession of an N-terminal sequence exhibiting some similarity to thaumatin-like proteins with antifungal activity, the lectin was devoid of antifungal activity. The lectin exerted some inhibitory effect on the glycohydrolases alpha-glucosidase, beta-glucosidase and beta-glucuronidase which are involved in HIV infection but had no suppressive action on human immunodeficiency virus-type 1 reverse transcriptase.
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PMID:A novel lectin from Pseudostellaria heterophylla roots with sequence simularity to Kunitz-type soybean trypsin inhibitor. 1144 23

A variety of lectins were tested in vitro for inhibitory action against the activities of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and the N-glycohydrolases (alpha-glucosidase, beta-glucosidase and beta-glucuronidase). Lectins from Phaseolus vulgaris, Momordica charantia, Ricinus communis and its constituent chains, and Agaricus bisporus were able to inhibit HIV-1 reverse transcriptase. P. vulgaris lectin and A. bisporus lectin were the most potent. The aforementioned lectins had only weak or no inhibitory effects on the glycohydrolases. The inhibitory effect of polysaccharopeptide from the mushroom Coriolus versicolor on HIV-1 reverse transcriptase and alpha-glucosidase was enhanced after chemical modification with chlorosulfonic acid. However, the inhibitory effect of the algal polysaccharide fucoidan on HIV-1 reverse transcriptase and alpha-glucosidase was not augmented by sulfation. Trypsin inhibitors from Phaseolus lunatus and Glycine max, gossypol and alkaloids from Corydalis yanhusuo were able to inhibit HIV-1 reverse transcriptase. Dicoumarol was capable of inhibiting HIV-1 reverse transcriptase, alpha-glucosidase, beta-glucosidase and beta-glucuronidase.
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PMID:Examination of lectins, polysaccharopeptide, polysaccharide, alkaloid, coumarin and trypsin inhibitors for inhibitory activity against human immunodeficiency virus reverse transcriptase and glycohydrolases. 1158 48

A homodimeric lectin adsorbed on Affi-gel blue gel and CM-Sepharose and possessing a molecular weight of 67 kDa was isolated from red kidney beans. The hemagglutinating activity of this lectin was inhibited by glycoproteins but not by simple sugars. The lectin manifested inhibitory activity on human immunodeficiency virus-1 reverse transcriptase and alpha-glucosidase. The N-terminal sequence of the lectin exhibited some differences from previously reported lectins from Phaseolus vulgaris but showed some similarity to chitinases. It exerted a suppressive effect on growth of the fungal species Fusarium oxysporum, Coprinus comatus, and Rhizoctonia solani. The lectin had low ribonuclease and negligible translation-inhibitory activities.
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PMID:Isolation of a homodimeric lectin with antifungal and antiviral activities from red kidney bean (Phaseolus vulgaris) seeds. 1173 88

1-Deoxynojirimycin (DNM) is a saccharide decoy that inhibits cellular alpha-glucosidase I-II activity. Treatment by DNM of human immunodeficiency virus (HIV)-infected lymphocyte cultures inhibits virus spread. The functional properties of the membrane-associated Env glycoprotein (Env) modified in the presence of DNM remain unclear because previous reports on this subject have essentially used recombinant soluble Envs whose properties differ notably from those of Env anchored on the surface of the virus. To model virus-associated Env synthesized in the presence of DNM, native Env was expressed at the surface of mammalian cells treated with DNM. As expected, its glycosylation pattern was altered in the presence of the inhibitor. Env was found able to bind CD4, whereas its ability to induce membrane fusion was abolished. The immunoreactivity of regions involved in interactions of Env with CXCR4 (V1, V2, C2, and V3) was modified and Env displayed altered interaction with this coreceptor. These results are consistent with the inhibition by DNM of virus entry at the Env/coreceptor interaction step. Finally, preliminary data indicate that suboptimal concentrations of DNM and natural or synthetic CXCR4 ligands used in combination potently inhibit the Env-mediated membrane fusion process. Altogether, our results suggest that DNM and its analogs deserve further investigation as anti-HIV agents in combination with experimental compounds targeting CXCR4 to inhibit each partner of this crucial step of HIV entry.
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PMID:The alpha-glucosidase inhibitor 1-deoxynojirimycin blocks human immunodeficiency virus envelope glycoprotein-mediated membrane fusion at the CXCR4 binding step. 1175 20


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