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)

Heteropolyoxotungstates of the Keggin class containing different heteroatoms were tested for inhibition of two strains of human immunodeficiency virus 1 (HIV-1); they exhibited varying antiviral activity. Compounds containing boron were inactive, only one of those containing phosphorus showed selective anti-viral activity, whereas all silicon-containing compounds exhibited significant anti-viral activity in C8166 cells infected with the IIIB strain. Their effectiveness was some 10-fold higher in JM cells with selectivity indices of about 2000. The silicotungstates were effective inhibitors of HIV reverse transcriptase, showing greater inhibition with RNA/DNA template primers than with DNA/DNA template.primer. Kinetic analysis demonstrated that they inhibit the enzyme by different mechanisms, as, of the four compounds examined, two competed with template.primer and two competed with deoxynucleoside triphosphate. Inhibition of DNA polymerase activity by these compounds was compared using polymerases from different sources, including human; although not necessarily most specific for HIV-1 reverse transcriptase, they did not inhibit all DNA polymerases to a similar degree.
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PMID:Anti-(human immunodeficiency virus) activity of polyoxotungstates and their inhibition of human immunodeficiency virus reverse transcriptase. 753 11

The human immunodeficiency virus, HIV-1, is generally accepted to be responsible for AIDS. It is imperative that all approaches, empirical and rational, be taken for development of a drug for therapy of this disease. These approaches are discussed, with emphasis on the direction being pursued in our laboratory. Empirically, we found 3'-deoxy-2',3'-didehydrothymidine, a compound first synthesized for potential anticancer activity by J. Horwitz in the 1960s, to be a potent inhibitor of HIV-1. It is now in Phase II/III clinical trials. We have also synthesized several 2,5'-anhydro pyrimidine nucleoside analogs, which have interesting chemical and biological properties. We have evaluated a natural product, gossypol and synthesized various derivatives for anti-HIV-1 activity, but none were appreciably more inhibitory than the parent compound. More recently, we have taken the rational approach and synthesized a boron-modified tetrapeptide, Ac-Thr-Leu-Asn-boro-Phe, which corresponds to the COOH-terminal of the Phe-Pro scissle bond of the gag/pol gene polyprotein product. Potent inhibition of the HIV-1 encoded protease was observed. These approaches and findings will be discussed.
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PMID:Empirical and rational approaches for development of inhibitors of the human immunodeficiency virus--HIV-1. 802 62

A novel 5-o-carboranyl-containing nucleoside, 5-o-carboranyl-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (6, CFAU), was synthesized as a potential intracellular neutron capture agent. This compound was prepared in five steps starting from 5-iodo-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (1). The desired carboranyl derivative was obtained by addition of decaborane [as the bis(propionitrile) adduct] to the protected acetylenic nucleoside precursor followed by debenzoylation. The synthesis of CFAU was also performed by glycosylation of the suitably protected 5-o-carboranyluracil with the appropriate 2-fluoroarabinosyl derivative. This compound was evaluated for its cytotoxicity in human lymphocytes, monkey cells, and rat and human gliomas cells, as well as for antiviral activity against human immunodeficiency virus and herpes simplex virus type 1. Its biological activity was compared to 5-o-carboranyl-1-(2-deoxyribofuranosyl)uracil in these cell culture systems, human bone marrow cells, and mice. The results obtained to date suggest that CFAU has suitable characteristics as a sensitizer for boron neutron capture therapy.
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PMID:Synthesis and biological properties of 5-o-carboranyl-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil. 805 1

Boronated oligonucleotides are potential candidates for boron neutron capture therapy, antisense technology, and as tools in molecular biology. The biological properties of dodecathymidylic acids containing one or more 5-(o-carboran-1-yl)-2'-deoxyuridine residues at different locations within the oligonucleotide chain were studied. 5-(o-Carboran-1-yl)-2'-deoxyuridine containing oligonucleotides manifested marked increased lipophilicity and resistance to 3'- or 5'-phosphodiesterases compared to the corresponding unmodified oligomer. They were substrates for T4 polynucleotide kinase and primers for Escherichia coli polymerase I and human immunodeficiency virus type 1 reverse transcriptase but not for human DNA polymerase alpha and beta. They also formed heteroduplexes that were substrates for E. coli RNase H, an essential property for antisense technology. These studies indicate that the carboranyl-containing oligonucleotides have desirable properties that need to be exploited further in the design of novel biopharmaceuticals.
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PMID:Carboranyl oligonucleotides. 3. Biochemical properties of oligonucleotides containing 5-(o-carboranyl-1-yl)-2'-deoxyuridine. 863 34

Peptides corresponding to the BH3 domains of Bax (BaxBH3) or Bcl-2 (Bcl2BH3) are potent inducers of apoptosis when fused to the Atennapedia plasma membrane translocation domain (Ant). BaxBH3Ant and Bcl2BH3Ant caused a mitochondrial membrane permeabilization (MMP) and apoptosis, via a mechanism that was not inhibited by overexpressed Bcl-2 or Bcl-X(L), yet partially inhibited by cyclosporin A (CsA), an inhibitor of the mitochondrial permeability transition pore. When added to isolated mitochondria, BaxBH3 and Bcl2BH3 induced MMP, which was inhibited by CsA. However, Bcl-2 or Bcl-X(L) failed to inhibit MMP induced by BaxBH3 and Bc2BH3 in vitro, while they efficiently suppressed the induction of MMP by the Vpr protein (from human immunodeficiency virus-1), a ligand of the adenine nucleotide translocator (ANT). BaxBH3 but not Bcl2BH3 was found to interact with ANT, and only BaxBH3 (not Bcl2BH3) permeabilized ANT proteoliposomes and induced ANT to form non-specific channels in electrophysiological experiments. In contrast, both BaxBH3 and Bcl2BH3 were able to stimulate channel formation by recombinant Bax protein. Thus, BaxBH3 might induce MMP via an action on at least two targets, ANT and Bax-like proteins. In contrast, Bcl2BH3 would elicit MMP in an ANT-independent fashion. In purified mitochondria, two ligands of ANT, bongkrekic acid and the protein vMIA from cytomegalovirus, failed to prevent MMP induced by BaxBH3 or Bcl2BH3. In conclusion, BaxBH3 and Bcl2BH3 induce MMP and apoptosis through a mechanism which overcomes cytoprotection by Bcl-2 and Bcl-X(L).
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PMID:Cell permeable BH3-peptides overcome the cytoprotective effect of Bcl-2 and Bcl-X(L). 1196 Mar 69

Programmed cell death--also known as apoptosis--has a crucial role in the immune system of mammals and other animals. It removes useless cells and potentially dangerous cells, including lymphocytes, and is involved in killing pathogen-infected or damaged cells. Defects in this process have been found to cause or contribute to diseases of the immune system, including immunodeficiency, autoimmunity, lymphoma and leukaemia. This review describes BH3-only proteins, a pro-apoptotic subgroup of the BCL-2 family, and their role in the development and function of the immune system.
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PMID:The role of BH3-only proteins in the immune system. 1571 25

Human immunodeficiency virus (HIV)-associated dementia is a neurodegenerative syndrome characterized by cognitive decline, personality change, and motor deficits. HIV-associated encephalitis (HAE), the neuropathology responsible for HIV-associated dementia, involves the formation of multinucleated giant cells or syncytia. In this article we describe the apoptotic pathways activated in the brains of HAE-affected patients. Approximately 50% of multinuclear giant cells exhibited apoptotic DNA fragmentation as detected by the terminal dUTP nick-end labeling technique. In addition, the presence of syncytia in the frontal cortex of approximately 35% of HAE patients correlated with the number of cells expressing the HIV-1 protein p24. Histochemical and immunohistochemical analyses revealed that HAE-associated syncytia underwent apoptosis through a mitochondrial pathway previously delineated for HIV-1 envelope-elicited syncytia in vitro. We observed over-expression of the mammalian target of rapamycin (mTOR), a kinase that mediates activation of the pro-apoptotic transcription factor p53, and p53-dependent up-regulation of two effectors of mitochondrial apoptosis, namely the BH3-only proteins Puma and transglutaminase type 2 (TG2). Interestingly, although mTOR activation and Puma induction were observed in dying syncytia and neurons, IkB phosphorylation and TG2 up-regulation were only found in syncytia. These findings provide substantial new information on the cell death mechanisms that regulate HAE, suggesting an important pathogenetic role of syncytia in the disease.
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PMID:Characterization of cell death pathways in human immunodeficiency virus-associated encephalitis. 1612 50

Apoptosis is essential for the development, function and homeostasis of the immune system. Experiments with transgenic and gene knock-out mice have shown that defects in the control of apoptosis in the hematopoietic system can promote the development of autoimmunity or hematological malignancy. In contrast, excessive apoptosis of normally long-lived hemopoietic cells can lead to lymphopenia and immunodeficiency. In mammals, cell death in response to developmental cues and many cell stress signals is regulated by the opposing factions of the Bcl-2 family of proteins. In particular, the pro-apoptotic subgroup called BH3-only proteins, which includes Bim, is critical in the initiation of apoptosis in response to many death stimuli. Bim has been found to be an important regulator of the negative selection of B lymphocytes in the bone marrow and of T lymphocytes both in the thymus and the periphery. Mice lacking Bim accumulate self-reactive lymphocytes, develop autoantibodies and on certain genetic backgrounds succumb to SLE-like autoimmune disease. Abnormalities in Bim expression and the thymic deletion of auto-reactive lymphocytes have also been implicated as a component of the complex, polygenic predisposition to autoimmune diabetes seen in NOD mice. Bim is also an essential regulator of T lymphocyte apoptosis during the termination of an immune response. This chapter focuses on the role of Bim in the development and function of the immune system and its potential role in autoimmunity. Degenerative disorders due to increased apoptosis mediated by Bim are also discussed.
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PMID:Role of Bim and other Bcl-2 family members in autoimmune and degenerative diseases. 1639 56

We describe here the synthesis of 9-[2-(boranophosphonomethoxy)ethyl]adenine (6a) and (R)-9-[2-(boranophosphonomethoxy)propyl]adenine (6b), the first alpha-boranophosphonate nucleosides in which a borane (BH3) group substitutes one nonbridging oxygen atom of the alpha-phosphonate moiety. H-phosphinates 5a and 5b and alpha-boranophosphonates 6a and 6b were evaluated for their in vitro activity against human immunodeficiency virus (HIV) infected cells and against a panel of DNA or RNA viruses. Compounds 5a, 5b, 6a, and 6b exhibited no significant antiviral activity in vitro and cytotoxicity. To measure the chemical and enzymatic stabilities of the target compounds 6a and 6b, kinetic data of decomposition for derivatives 5a, 5b, 6a, 6b, and standard compounds were studied at 37 degrees C in several media. The alpha-boranophosphonates 6a and 6b were metabolized in culture medium into H-phosphinates 5a and 5b, with half-live values of 5.3 h for 6a and 1.3 h for 6b.
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PMID:Synthesis, in vitro antiviral evaluation, and stability studies of novel alpha-borano-nucleotide analogues of 9-[2-(phosphonomethoxy)ethyl]adenine and (R)-9-[2-(phosphonomethoxy)propyl]adenine. 1718 Nov 62

A diamond-like carbon (DLC) microelectrode was applied to commercial ELISA kits for medical diagnosis of HIV (human immunodeficiency virus), HBV (human hepatitis B virus), HCV (human hepatitis C virus). In this work, quantification of oxidized 3,3',5,5'-tetramethylbenzidine (TMB) was carried out by using a microelectrode made of boron-doped DLC and cyclic voltammetric analysis method without the conventional quenching step which uses sulfuric acid. The microelectrode provided well-known step-shaped graphs, and limit of detection could be improved by clear determination of electrochemical oxidative and reductive peaks. To demonstrate the applicability of DLC microelectrode to conventional ELISA kits, commercial ELISA kits for detection of HIV antigen, HBV antigen and HCV antigen were also tested. These results proved that the applicability of DLC microelectrode to practical detection is feasible.
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PMID:Diamond-like carbon (DLC) microelectrode for electrochemical ELISA. 1880 87


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