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: EC:3.4.21.1 (chymotrypsin)
10,938 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The replacement of genetically deficient enzymes in patients with inherited metabolic disorders by infusion of purified enzymes or by organ transplantation has had very limited success, although good results with bone marrow transplantation have been obtained in some patients with mucopolysaccharidosis, Gaucher disease and inherited immunodeficiency diseases. Genetic engineering of the patient's lymphocytes may ultimately render these approaches redundant, at least for some of these diseases. Treatment of chronic pancreatic insufficiency and of disaccharidase deficiency with oral enzymes can be very effective; therapy can be monitored in the latter by measuring the breath hydrogen excretion and in the former by a range of tests of which stool chymotrypsin assay is the most convenient. Treatment of acute myocardial infarction by intracoronary perfusion of thrombolytic enzymes can improve both cardiac function and long-term survival if given early enough. Successful reperfusion can be identified by changes in the kinetics of serum enzyme release and clearance, especially for the isoenzymes and isoforms of creatine kinase. In cancer chemotherapy, L-asparaginase has long been a useful adjunct in the treatment of acute lymphoblastic leukemia, but recent experience suggests a role in acute nonlymphoblastic leukemia as well.
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PMID:Enzymes as agents for the treatment of disease. 157 79

Retroviral RNA-dependent DNA polymerase (reverse transcriptase or RT) uses the 3'OH end of a cellular tRNA as primer to initiate DNA synthesis. Previous work with avian retrovirus has shown that reverse transcriptase is implicated in the selection of cellular virion-encapsidated tRNAs and has shown that the primer tRNA is positioned on the primer binding site near the 5' end of the viral RNA. These mechanisms support the idea that the retroviral polymerase should form complexes with primer tRNA and the specific encapsidated ones. The genomic sequence of human immunodeficiency virus (HIV) allows the prediction that tRNA(Lys3) is the natural primer. In this article we show, using the mobility shift assay, that recombinant HIV reverse transcriptase is able to form a complex with bovine tRNA(Lys.) By fluorescence studies and alpha-chymotrypsin analysis we have observed a modification of the enzyme conformation when reverse transcriptase is bound to the putative primer tRNA. This structural change is specific for tRNA(Lys) although the retroviral polymerase is able to interact with other tRNAs.
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PMID:Interactions with tRNA(Lys) induce important structural changes in human immunodeficiency virus reverse transcriptase. 170 35

A principal neutralizing domain (PND) of the major envelope glycoprotein (gp120) of the HTLV-III BH10 strain of human immunodeficiency virus type 1 (HIV-1) has significant amino acid similarities to a reactive site of Kunitz-type basic proteinase inhibitors. We therefore thought that the PND may interact with cellular proteinase-like molecule(s) upon HIV-1 infection and measured the cellular proteolytic activities at the surface of intact Molt-4 clone 8 cells, which are highly susceptible to HIV-1 infection. The cells preferentially cleaved succinyl-Leu-Leu-Val-Tyr-4-methylcoumaryl-7-amide, a good substrate of chymotrypsin, and the activity was strongly inhibited by N-tosyl-L-phenylalanyl chloromethyl ketone (IC50 = 11.5 microM) and chymostatin (IC50 = 4.8 microM). A synthetic peptide of 24 residues (amino acids 308-331) that correspond to the PND also inhibited the cellular proteolytic activity in a dose-dependent manner (IC50 = 79.2 microM). The inhibition was still observed at low temperature (IC50 = 42.7 microM) and even after the peptide-treated cells were washed. We therefore think that the peptide interacts with proteinase-like molecule(s) located at the surface of the cells. The synthetic peptides from four other strains of HIV-1 corresponding to the PND similarly inhibited the proteolytic activity. These results may be helpful to clarify the novel mechanism(s) for HIV-1 infection.
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PMID:A principal neutralizing domain of human immunodeficiency virus type 1 interacts with proteinase-like molecule(s) at the surface of Molt-4 clone 8 cells. 191 51

Human immunodeficiency virus (HIV)-infected multinucleated giant cells previously were detected only in the central nervous system of HIV-positive patients. Reported here are the first cases in which such infected cells were observed outside the central nervous system, in the oropharyngeal lymphoid tissues. Tonsils and adenoids were removed individually from two asymptomatic homosexual men. Follicular hyperplasia and many interfollicular multinucleated giant cells most often in contact with or in close proximity of the mucous membrane were seen. The latter were positive for lysozyme, alpha-1 anti-chymotrypsin, OKM1, and S-100 protein in accordance with a histiocytic origin. In situ hybridization with an HIV envelope-specific RNA probe demonstrated the presence of viral RNA in these multinucleated giant cells. These findings support the role of peripheral histiocytes as a primary virus reservoir early in the disease. They also underline the potential role of oropharyngeal tissue as a primary target in some cases.
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PMID:Human immunodeficiency virus-infected multinucleated histiocytes in oropharyngeal lymphoid tissues from two asymptomatic patients. 199 67

Persistent infection by human immunodeficiency virus (HIV-1) in the chimpanzee may be valuable for immunopathologic and potential vaccine evaluation. Two HIV strains, the tissue culture-derived human T-cell lymphotropic virus type IIIB (HTLV-IIIB) and in vivo serially passaged lymphadenopathy-associated virus type 1 (LAV-1), were injected intravenously into chimpanzees. Two animals received HTLV-IIIB as either virus-infected H9 cells or cell-free virus. A third animal received chimpanzee-passaged LAV-1. Evaluation of their sera for virus-specific serologic changes, including neutralizations, was done during a 2-year period. During this period all animals had persistently high titers of antibodies to viral core and envelope antigens. All three animals developed a progressively increasing type-specific neutralizing LAV-1 versus HTLV-IIIB antibody titer during the 2-year observation period which broadened in specificity to include HTLV-HIRF, HTLV-IIIMN, and HTLV-IIICC after 6 to 12 months. The antibody titers against both viruses were still increasing by 2 years after experimental virus inoculation. Sera from all animals were capable of neutralizing both homologously and heterologously reisolated virus from chimpanzees. A slightly more rapid type-specific neutralizing response was noted for the animal receiving HTLV-IIIB-infected cells compared with that for cell-free HTLV-IIIB. Sera from all persistently infected chimpanzees were capable of mediating group-specific antibody-mediated complement-dependent cytolysis of HIV-infected cells derived from all isolates tested. Viruses reisolated from all three animals at 20 months after inoculation revealed very similar peptide maps of their respective envelope gp120s, as determined by two-dimensional chymotrypsin oligopeptide analysis. One peptide, however, from the original HTLV-IIIB-inoculated virus was deleted in viruses from all three animals, and in addition, we noted the appearance of a new or modified peptide which was common to LAV-1 as well as to HTLV-IIIB reisolated from infected chimpanzees. It thus appears that a group-specific neutralizing antibody response as well as a group-specific cytotoxic response can develop in chimpanzees after an inoculation of a single HIV variant. This finding suggests that a common, less immunodominant determinant(s) is present on a single HIV strain which could induce group-specific antibodies during viral infection and replication. The identification of this group-specific epitope and the induction of analogous immunity may be relevant to vaccine development against human acquired immunodeficiency syndrome.
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PMID:Persistent infection of chimpanzees with human immunodeficiency virus: serological responses and properties of reisolated viruses. 244 11

The envelope protein of human immunodeficiency virus (HIV) is synthesized as a polyprotein (gp160) and cleaved intracellularly to a gp120-gp41 heterodimer. In this study, the tryptic-like endoproteolytic cleavage site was removed by site-directed mutagenesis and replaced with a chymotryptic-like site. The resultant mutant, RIP7/mut10, was found to be indistinguishable from wild-type HIV when analyzed at the level of proviral replication, RNA processing, protein expression, and viral assembly. However, the gp160 polyprotein was not cleaved and the mutated virions were biologically inactive, until and unless they were exposed to limiting concentrations of chymotrypsin. As is the case for other enveloped mammalian viruses, endoproteolytic cleavage of the HIV envelope protein and release of a unique hydrophobic domain appear to be necessary for the full expression of viral infectivity.
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PMID:Endoproteolytic cleavage of gp160 is required for the activation of human immunodeficiency virus. 245 Jun 79

Unusual cutaneous vascular neoplasms distinct from Kaposi's sarcoma were observed in five patients with the acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV)-1 infection. The cutaneous lesions were solitary or multiple papules and nodules. In some patients the lesions also affected internal organs. Histologically the neoplasms were composed of proliferating blood vessels and cells with epithelioid features. Immunoperoxidase studies of one lesion showed that the cells expressed both factor VIII antigen, a maker for endothelial cells, and alpha 1-anti-chymotrypsin, a marker for histiocytes. In some patients the lesions gradually disappeared but in two they were the cause of death, in one case from disseminated intravascular coagulation and in the other from laryngeal obstruction by the tumour.
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PMID:Epithelioid angiomatosis: a distinct vascular disorder in patients with the acquired immunodeficiency syndrome or AIDS-related complex. 288 42

A new trypsin-like serine protease was cloned from both a murine cytotoxic T lymphocyte and a human PHA-stimulated peripheral blood lymphocyte cDNA library. In both the mouse and human system, this transcript had a T cell- and NK-specific distribution, being detected in cytotoxic T lymphocytes (CTL), some T-helper clones, and NK, but not in a variety of normal tissues. T-cell activation with Con A plus IL-2 induced mouse spleen cells to express this gene with kinetics correlating with the acquisition of cytolytic capacity. Both the mouse and human nucleotide sequences of this gene encoded an amino acid sequence with 25-40% identity to members of the serine protease family. The active-site "charge-relay" residues (His-57, Asp-102, and Ser-195 of the chymotrypsin numbering system) are conserved, as well as the trypsin-specific Asp (position 189 in trypsin). We reviewed the evidence of this serine protease's role in lymphocyte lysis and proposed a "lytic cascade." We discussed the biological and clinical implications of a cascade, proposing these enzymes as markers for cytolytic cells and as targets for rational drug therapy. Genetic and acquired deficits in the lethal hit-delivery system are considered as a basis for approaching some immunodeficiency states, including severe EBV infections, T-gamma leukemias, and T8+ lymphocytosis syndromes.
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PMID:A T cell- and natural killer cell-specific, trypsin-like serine protease. Implications of a cytolytic cascade. 305 12

Infection of monocyte-macrophages with human immunodeficiency virus may be central to the pathogenesis of the acquired immunodeficiency syndrome. The ability of infected macrophages to prime T cells through IL-1 production was investigated in vitro. Purified human monocytes maintained in suspension culture were infected with strain HIV-DV. Intracellular expression of virus p24 antigen increased from undetectable levels immediately after infection to 13-59% of cells by 10-14 d; infected macrophages remained viable for up to 60 d. Supernatants collected between 14 and 20 d after infection were examined in the murine thymocyte co-mitogenesis assay and demonstrated to contain a potent IL-1 inhibitor, designated contra-IL-1. Contra-IL-1 activity was present in all supernatants examined after 4 d of infection, and peaked coincident with peak p24 antigen expression. Inhibitory activity was not present in uninfected cells. Contra-IL-1 activity eluted after gel filtration with an approximate molecular weight of 9 kD. Inhibitory activity was removed by exposure to heat or acid pH, or by incubation with chymotrypsin or staphylococcal V8 protease. Contra-IL-1 did not inhibit IL-2- or IL-4-dependent proliferation of murine T cell lines. Despite its ability to inhibit IL-1 activity, contra-IL-1 did not interfere with the binding of recombinant IL-1 beta to a fibroblast cell line. Contra-IL-1 inhibited the proliferation of normal peripheral blood mononuclear cells to both concanavalin A and tetanus toxoid; inhibition could be attenuated by the addition of exogenous IL-1. Messenger RNA extracted from infected macrophages was examined by Northern analysis for the presence of message to IL-1 beta. No message was apparent, suggesting that the presence of contra-IL-1 was not obscuring the concomitant release of IL-1. Infected macrophages stimulated with endotoxin generated readily detectable message for IL-1 beta. Spleen macrophages purified from two patients with AIDS complicated by immune thrombocytopenia spontaneously expressed p24 antigen in vitro and released contra-IL-1 activity into the media. Contra-IL-1 may contribute to the immune dysfunction of AIDS.
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PMID:Release of interleukin 1 inhibitory activity (contra-IL-1) by human monocyte-derived macrophages infected with human immunodeficiency virus in vitro and in vivo. 326 91

DMP 323 is a potent inhibitor of the protease of human immunodeficiency virus (HIV), with antiviral activity against both HIV type 1 and HIV type 2. This compound is representative of a class of small, novel, nonpeptide cyclic urea inhibitors of HIV protease that were designed on the basis of three-dimensional structural information and three-dimensional database searching. We report here studies of the kinetics of DMP 323 inhibition of the cleavage of peptide and HIV-1 gag polyprotein substrates. DMP 323 acts as a rapidly binding, competitive inhibitor of HIV protease. DMP 323 is as potent against both peptide and viral polyprotein substrates as A-80987, Q8024, and Ro-31-8959, which are among the most potent inhibitors of HIV protease described in the literature to date. Incubation with human plasma or serum did not decrease the effective potency of DMP 323 for HIV protease, suggesting that plasma protein binding is of a low affinity relative to that of HIV protease. DMP 323 was also assessed for its ability to inhibit the mammalian proteases renin, pepsin, cathepsin D, cathepsin G, and chymotrypsin. No inhibition of greater than 12% was observed for any of these enzymes at concentrations of DMP 323 that were 350 to 40,000 times higher than that required to inhibit the viral protease 50%.
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PMID:Potency and selectivity of inhibition of human immunodeficiency virus protease by a small nonpeptide cyclic urea, DMP 323. 797 96


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