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)

Various cellular stress agents like ionizing radiation exposure could activate human immunodeficiency virus type 1 (HIV- 1) replication or reporter gene expression. In addition, extracellular factor(s) released by X-ray-treated human colonic carcinoma cell line (HT29) might activate the long terminal repeat (LTR) of HIV-1 in non-irradiated HT29 cells. In the present report we show that in various transiently or stably transfected cell lines, X-ray irradiation up-regulates HIV-1 LTR transcription through the kappaB regulatory elements. A factor(s), which is processed by and acts upon a variety of cell types, was detected by addition to non-irradiated cells of either X-ray-treated cells or a conditioned medium taken from irradiated cultures. The magnitude of responsiveness is cell type dependent. In addition, X-ray activation of HIV-1 LTR in transiently or stably transfected cell lines is inhibited by a potent antioxidant drug, pyrrolidine dithiocarbamate and by another drug, known for its role in the trapping of growth factors, suramin. The importance of these observations in the pathophysiology of patients with AIDS-related cancers treated by radiotherapy remains to be established.
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PMID:X-rays-induced secretion of cellular factor(s) that enhance(s) HIV-1 promoter transcription in various non-irradiated transfected cell lines. 987 15

Pyrrolidine dithiocarbamate (PDTC) has been widely used as an inhibitor of the nuclear factor-kappa B, (NF-kappa B) signalling pathway. Here, we show that kappa B-dependent reporter gene expression induced by low concentrations of 12-O-tetradecanoylphorbol-13-acetate (TPA) is potentiated by PDTC in the human pro-monocytic U937 cell line. The stimulatory effect of PDTC on kappa B-dependent gene expression was shown with a 4 x kappa B chloramphenicol acetyltransferase construct and required an intact kappa B element in the human immunodeficiency virus long terminal repeat (HIV-1 LTR). Unexpectedly, an HIV-1 LTR construct with a mutation of the activator protein 2 (AP-2) binding site located between the two kappa B elements was unresponsive to the stimulatory effect of PDTC with TPA. The stimulation or inhibition of kappa B-dependent gene expression was dependent on PDTC pre-treatment and the concentration of TPA. No stimulatory effect on HIV-1 LTR activity was observed with the metal chelator dipyridyl or the anti-oxidant N-acetyl-L-cysteine. These results are consistent with the hypothesis that PDTC treatment potentiated kappa B-dependent gene expression in a manner dependent on the concentration of TPA.
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PMID:Dual activity of pyrrolidine dithiocarbamate on kappa B-dependent gene expression in U937 cells: I. Regulation by the phorbol ester TPA. 1040 58

The structures of two potential anti-human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTI), namely 1-(2-chlorobenzoyl)-2-phenylpyrrolidine-2-carboxamide, C(18)H(17)ClN(2)O(2), and 1-(2-furoyl)-2-phenylpyrrolidine-2-carboxamide, C(16)H(16)N(2)O(3), have been investigated by X-ray diffraction and the butterfly-like conformation established in each case. The pyrrolidine ring has the same half-chair conformation in both structures.
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PMID:1-Substituted derivatives of 2-phenylpyrrolidine-2-carboxamide. 1209 54

The structures of two potential anti-human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTI), namely 1-benzyl-5-oxo-2-phenylpyrrolidine-2-carboxamide, C(18)H(18)N(2)O(2), (III), and 2-(4-isopropoxyphenyl)-5-oxo-1-(4-tolyl)pyrrolidine-2-carbonitrile, C(21)H(22)N(2)O(2), (IV), have been investigated by X-ray diffraction, confirming the butterfly-like conformation of both compounds. The pyrrolidine ring is in an envelope conformation in (III) and a half-chair conformation in (IV). Two intermolecular N[bond]H...O hydrogen bonds are present in the crystal structure of (III), with N...O distances of 2.995 (2) and 2.927 (2) A.
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PMID:1-Substituted derivatives of 2-aryl-5-oxopyrrolidine-2-carboxylic acid. 1209 58

The pyrrolidine alkaloids mimicking the structures of pentose with nitrogen in the ring are known to be inhibitors of glycosidases. We report here that a compound belonging to this category is an inhibitor of eukaryotic DNA polymerases. Among the eight naturally occurring pyrrolidine alkaloids we tested, only one compound, 1,4-dideoxy-1,4-imino-D-ribitol (DRB), which was purified from the mulberry tree (Morus alba), strongly inhibited the activities of eukaryotic DNA polymerases with IC50 values of 21-35 microM, and had almost no effect on the activities of prokaryotic DNA polymerases, nor DNA metabolic enzymes such as human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase, and bovine deoxyribonuclease I. Kinetic studies showed that inhibition of both DNA polymerases alpha and beta by DRB was competitive with respect to dNTP substrate. Whereas DNA polymerase alpha inhibition was noncompetitive with the template-primer, the inhibition of DNA polymerase beta was found to be competitive with the template-primer. The K(i) values of DNA polymerases alpha and beta for the template-primer were smaller than those for dNTP substrate. Therefore, the affinity of DRB was suggested to be higher at the template-primer binding site than at the dNTP substrate-binding site, although DRB is an analogue of deoxyribose consisting of dNTP. Computational analyses of the eight pyrrolidine alkaloids revealed a remarkable difference in the distribution of positive and negative electrostatic charges on the surface of molecules. The relationship between the structure of DRB and the inhibition of eukaryotic DNA polymerases is discussed.
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PMID:The inhibitory action of pyrrolidine alkaloid, 1,4-dideoxy-1,4-imino-D-ribitol, on eukaryotic DNA polymerases. 1270 87

2-(1-Adamantyl)pyrrolidines 6, 7, 2-(1-adamantyl)piperidines 10, 12a-c, 15a,b and 2-(1-adamantyl)hexahydroazepines 19, 21, 22 were synthesized and tested for their antiviral activity against influenza A, B viruses and the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The synthetic procedure followed for the preparation of the parent piperidine 10 represents a general method for the synthesis of 2-alkyl- or cycloalkyl-substituted piperidine alkaloids. Parent aminoadamantanes 6, 10 and 19 contain the 1-aminoethyl pharmacophore group of rimantadine drug 2, extended into a saturated nitrogen heterocycle: pyrrolidine, piperidine and hexahydroazepine, respectively. The ring size effect in anti-influenza A activity was investigated. Rimantadine analogues 6 and 10 were, respectively, 6- and 4-fold more active than the drug Rimantadine 2, whereas the hexahydroazepine derivative 19 was inactive. Thus, enlargement from a 5-(pyrrolidine)- or 6-(piperidine)- to a 7-(hexahydroazepine)- membered heterocyclic ring dramatically reduced the anti-influenza virus A activity. Substitution of piperidine 10 with a dialkyaminoethyl group led to the active compounds 15a and 15b: compound 15a was active against influenza A virus whereas both 15a and 15b were active against HIV-1.
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PMID:Heterocyclic rimantadine analogues with antiviral activity. 1464 92

The structures of the potential anti-human-immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTI) 1-tert-butoxycarbonyl-2-phenylpyrrolidine-2-carboxylic acid, C(16)H(21)NO(4), (I), and 2-ammoniomethyl-1-benzyl-5-oxo-2-phenylpyrrolidine chloride, C(18)H(21)N(2)O(+).Cl(-), (II), have been investigated by X-ray diffraction. The investigations confirm a butterfly-like conformation for both compounds. In (I), the pyrrolidine ring has a marked half-chair conformation, while it has a weakly pronounced envelope conformation in (II). Intermolecular hydrogen bonds, viz. O-H.O in (I), and N-H.O and N-H.Cl in (II), build infinite chains in both structures. Rotational disorder of the three methyl groups is observed in (I).
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PMID:1,2,5-Substituted derivatives of 2-phenylpyrrolidine. 1517 59

Expression of cell adhesion molecule in endothelial cells upon activation by human immunodeficiency virus (HIV) infection is associated with the development of atherosclerotic vasculopathy. We postulated that induction of vascular cell adhesion molecule-1 (VCAM-1) by HIV-1 Tat protein in endothelial cells might represent an early event that could culminate in inflammatory cell recruitment and vascular injury. We determined the role of HIV-1 Tat protein in VCAM-1 expression in human pulmonary artery endothelial cells (HPAEC). HIV-1 Tat protein treatment significantly increased cell-surface expression of VCAM-1 in HPAEC. Consistently, mRNA expression of VCAM-1 was also increased by HIV-1 Tat protein as measured by RT-PCR. HIV-1 Tat protein-induced VCAM-1 expression was abolished by the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) and the p38 MAPK inhibitor SB-203580. Furthermore, HIV-1 Tat protein enhanced DNA binding activity of NF-kappaB, facilitated nuclear translocation of NF-kappaB subunit p65, and increased production of reactive oxygen species (ROS). Similarly to VCAM-1 expression, HIV-1 Tat protein-induced NF-kappaB activation and ROS generation were abrogated by PDTC and SB-203580. These data indicate that HIV-1 Tat protein is able to induce VCAM-1 expression in HPAEC, which may represent a pivotal early molecular event in HIV-induced vascular/pulmonary injury. These data also suggest that the molecular mechanism underlying the HIV-1 Tat protein-induced VCAM-1 expression may involve ROS generation, p38 MAPK activation, and NF-kappaB translocation, which are the characteristics of pulmonary endothelial cell activation.
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PMID:HIV-1 Tat protein-induced VCAM-1 expression in human pulmonary artery endothelial cells and its signaling. 1580 38

Human immunodeficiency virus-1 gp120 alters astroglial function, which compromises the function of the nearby of neuronal cells contributing to the cognitive impairment in human immunodeficiency virus-1 infection. Cyclooxygenase (COX)-2 has been involved in this process, although the intracellular pathways and second messengers involved are yet unknown. We have investigated the role of gp120-induced COX-2 in the astrocytoma human cell line U-87, and the different pathways involved in this activation. COX-2 mRNA and protein expression were detected in gp120-stimulated cells. Moreover, gp120 induces COX-2 promoter transcription. The effect of gp120 was abrogated by a neutralizing antibody against the chemokine receptor CXCR4 neutralizing antibody. Analysis of the promoter show that deletion or mutation of a proximal nuclear factor (NF)-kappaB site completely abrogated gp120-dependent transcription. NF-kappaB but neither Activating protein-1 nor nuclear factor of activated T-cells-dependent transcription was induced by gp120, as shown by reporter and electrophoretic mobility shift assays. In addition, transfection assays with the NF-kappaB inhibitor, IkappaBalpha, prevented gp120-mediated COX-2 induction. In contrast, there was no inhibition of COX-2 promoter transcription by expressing a dominant negative c-Jun, or nuclear factor of activated T-cells constructs. The antioxidant pyrrolidine dithiocarbamate inhibited COX-2 protein expression and COX-2 transcriptional activity induced by gp120. Thus, our results indicate that gp120 induced COX-2 transcription through NF-kappaB activation in astrocytoma cells.
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PMID:HIV-1 envelope glycoprotein 120 induces cyclooxygenase-2 expression in astrocytoma cells through a nuclear factor-kappaB-dependent mechanism. 1762 37

Infections with the human immunodeficiency virus, which inevitably lead to the development of AIDS, are still among the most serious global health problems causing more than 2.5 million deaths per year. In the pathophysiological processes of this pandemic, HIV protease has proven to be an invaluable drug target because of its essential role in the virus' replication process. By use of pyrrolidine as core structure, symmetric 3,4-bis-N-alkylsulfonamides were designed and synthesized enantioselectively from D-(-)-tartaric acid as a new class of HIV protease inhibitors. Structure-guided design using the cocrystal structure of an initial lead as starting point resulted in a second series of inhibitors with improved affinity. The binding modes of four representatives were determined by X-ray crystallography to elucidate the underlying factors accounting for the SAR. With this information for further rational design, the combination of suitable side chains resulted in a final inhibitor showing a significantly improved affinity of K(i) = 74 nM.
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PMID:Structure-guided design of C2-symmetric HIV-1 protease inhibitors based on a pyrrolidine scaffold. 1834 17


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