UMLS:C0021051 - FACTA Search

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

Replication of human immunodeficiency virus requires binding of the viral Tat protein to its RNA target sequence TAR; peptides derived from Tat bind to a TAR "contact site" spanning 5 bp and a trinucleotide pyrimidine bulge. We find that high affinity binding requires a U residue in the bulge loop and 2 specific adjacent base pairs. Other bulged RNAs bind in a lower affinity nonspecific manner; sequence-specific binding requires a bulge loop of more than 1 nucleotide. Reaction with diethyl pyrocarbonate indicates that one effect of the bulge is to make the otherwise deep and narrow RNA major groove accessible. A model consistent with these data involves local distortion of A-form geometry at the bulge, which bends the helix and permits protein binding and interactive access in the RNA major groove.
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PMID:RNA recognition by Tat-derived peptides: interaction in the major groove? 190 91

The inhibitory effects of a series of antiviral compounds on human immunodeficiency virus type 1 (HIV-1) were evaluated in a plaque assay (PA) in MT-4 cells and a focal immunoassay (FIA) in CD4+ HeLa cells. Similar 50% inhibitory concentrations (IC50) were obtained for the sulfated polysaccharides when measured by PA or FIA: the IC50 values of dextran sulfate and pentosan polysulfate were 0.8 microgram/ml and 0.35 microgram/ml, respectively. Also, comparable IC50 values (ranging from 1.42 to 2.71 microM) were obtained for purine 2',3'-dideoxyribosides (i.e. DDA, DDI and DDG) when evaluated by PA or FIA. In contrast, the IC50 values of pyrimidine 2',3'-dideoxyribosides were invariably 4- to 10-fold lower when monitored by PA than FIA: the IC50s of AZT, D4T and DDC in the PA were 0.015, 0.094 and 0.038 microM, respectively, and in the FIA were 0.062 microM, 0.29 microM and 0.46 microM, respectively. The differential anti-HIV-1 activities found with AZT, D4T and DDC in the PA and FIA systems may at least be related in part to differences in the metabolism of the compounds (i.e. phosphorylation by thymidine kinase or 2'-deoxycytidine kinase) between MT-4 and CD4+ HeLa cells. The novel anti-HIV-1 compounds tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (TIBO) derivatives, R82150 and R82913, and the acyclouridine derivative 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine (HEPT) were also more inhibitory to HIV-1 in the PA than FIA system. The IC50 values of R82150, R82913 and HEPT, as based on PA, were 0.005, 0.003 and 0.79 microM, respectively. Their IC50 values, as based on FIA, were 0.020 microM, 0.015 microM and 3.77 microM, respectively. The TIBO derivatives emerged as the most effective HIV-1 inhibitors of the compounds tested whether assayed by PA or FIA.
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PMID:Anti-HIV-1 activity of antiviral compounds, as quantitated by a focal immunoassay in CD4+ HeLa cells and a plaque assay in MT-4 cells. 198 Jan 26

A range of 2'-fluoro and 2',3'-difluoro analogues of pyrimidine deoxyribonucleosides have been synthesized and evaluated against human immunodeficiency virus (HIV-1) in a human lymphoblastoid cell line. Among these compounds, 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12), 2',3'-didehydro-2',3'-dideoxy-2'-fluorocytidine (35), 1-(2,3-dideoxy-2,3-difluoro-beta-D-arabinofuranosyl)cytosine (41), and 3'-deoxy-2',3'-didehydro-2'-fluorothymidine (45) were found to have significant antiviral activity, with IC50 values of 0.65, 10, 10, and 100 microM, respectively. The structure-activity relationships are discussed.
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PMID:Synthesis and antiviral activity of monofluoro and difluoro analogues of pyrimidine deoxyribonucleosides against human immunodeficiency virus (HIV-1). 216 61

Several 2'-fluoroarabino-2',3'-dideoxy- and 2'-fluoro-2',3'-unsaturated 2',3'-dideoxy pyrimidine nucleoside analogues are reported. The saturated analogues 1-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)thymine (2'-threo-FddT, 33), 1-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)uracil (2'-threo-FddU, 22) were readily prepared from the corresponding 2'-deoxy-2'-fluoroarabinosyl nucleoside analogue by radical deoxygenation of the 3'-OH. The unsaturated compounds 1-(2,3-dideoxy-2-fluoro-beta-D-glycero-pent-2-enofuranosyl)thymine (2'-Fd4T, 40) and 1-[5-O-(mono-methoxytrityl)-2-fluoro-2,3-dideoxy-beta-D-glycero-pen t-2- enofuranosyl]uracil (39) were synthesized by an elimination reaction of the O-2,3'-anhydro-2'-fluoro-lyxo derivatives under basic conditions. The cytidine analogues 28 and 41 were prepared by amination of the corresponding uridine derivatives; compounds 28 and 41 were deprotected to give 1-(2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)cytidine (2'-threo-FddC, 29) and 1-(2,3-dideoxy-2-fluoro-beta-D-glycero-pent-2- enofuranosyl)cytosine (2'-Fd4C, 42), respectively. All of these novel compounds were evaluated in vitro against human immunodeficiency virus (HIV) (LAV isolate). 2'-threo-FddC (29) was the most active of the newly synthesized substances against HIV with an ID50 of 0.8 microgram/mL; ddC had an ID50 of 0.007 micrograms/mL. Because of its potency in the initial tests, 29 was further evaluated in both T cells and macrophage/monocyte cell lines, with several different isolates of HIV. Although 2'-threo-FddC (29) exhibited good antiviral activity in these systems it was less active than AZT in these assays. At 1 microM the inhibition of CFU-GM by 29 was found to be 35-40%; this is slightly higher than seen with AZT.
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PMID:Synthesis and anti-HIV activity of several 2'-fluoro-containing pyrimidine nucleosides. 216 62

This review delineates the subcellular distribution, biochemical characteristics, and metabolic functions of 5'-nucleotidase (5'NT), summarizes the analytical biochemistry of 5'NT, and assesses the clinical significance of 5'NT determinations in body fluids, cells, and tissues. Salient aspects of the clinical biochemistry of 5'NT, discussed herein, are as follows: (A) Serum 5'NT activity is generally elevated in hepatobiliary diseases, especially with intrahepatic obstruction, but, unlike serum alkaline phosphatase, serum 5'NT activity is not increased in infancy, childhood, pregnancy, or osteoblastic disorders. (B) In cancer patients, elevated serum 5'NT activity does not always indicate hepatobiliary involvement; in some cases, 5'NT may be released into serum from the primary tumor or local metastases. (C) Genetic deficiency of erythrocyte pyrimidine 5'NT activity is a common cause of hereditary non-spherocytic hemolytic anemia. (D) Acquired deficiency of erythrocyte pyrimidine 5'NT activity occurs in patients with beta-thalassemia and lead poisoning. (E) 5'NT activity is low in circulating monocytes, increases markedly upon their differentiation to tissue macrophages, and subsequently diminishes during macrophage activation. (F) Lymphocyte ecto-5'NT activity, a plasma membrane marker of cell maturation, is generally low in immunodeficiency states, and undergoes characteristic changes in patients with certain lymphomas and leukemias.
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PMID:The clinical biochemistry of 5'-nucleotidase. 218 4

The general physical characteristics and replication of retroviruses are considered, along with assays for viral products. The specific agent for acquired immunodeficiency syndrome, the human immunodeficiency virus (HIV), is characterized as a lentivirus causing persistent, lifelong infection. While human immunodeficiency virus retroviruses share many of the same properties as other replication-competent viruses, genetic variability occurs among HIV isolates, and this variability may have a considerable effect on the virus' virulence, cell type specificity, viral susceptibility to antiviral compounds, clinical presentation, and disease progression. The most notable difference between HIV replication and other retroviruses is the intricate control of HIV gene expression by viral and cellular factors. Possible mechanisms by which HIV kills infected cells include the formulation of multinucleate syncytia; cytopathic components within the virions themselves; and interaction between viral envelope proteins and the CD4 molecule on the cell surface. Agents shown to inhibit viral replication at the level of the reverse transcriptase are phosphonoformate, sulfated polysaccharides, rifabutin, and nucleoside analogs, as well as purine and pyrimidine analogs. To date, only one nucleoside analog, zidovudine, has demonstrated clear clinical benefit and anti-HIV activity.
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PMID:Biology of retroviruses: detection, molecular biology, and treatment of retroviral infection. 219 45

Proteolytically produced carboxyl-terminal fragments of the human immunodeficiency virus type-1 (HIV-1) Tat protein that include a conserved region rich in arginine and lysine bind specifically to transactivation response RNA sequences (TAR). A chemically synthesized 14-residue peptide spanning the basic subdomain also recognizes TAR, identifying this subdomain as central for RNA interaction. TAR RNA forms a stable hairpin that includes a six-residue loop, a trinucleotide pyrimidine bulge, and extensive duplex structure. Competition and interference experiments show that the Tat-derived fragments bind to double-stranded RNA and interact specifically at the pyrimidine bulge and adjacent duplex of TAR.
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PMID:Fragments of the HIV-1 Tat protein specifically bind TAR RNA. 220 2

Mitsuya and Broder [Proc. Natl. Acad. Sci. USA 83:1911-1915 (1986)] demonstrated that every purine (adenosine, guanosine, and inosine) and pyrimidine (cytidine and thymidine) nucleoside containing the 2',3'-dideoxyribose configuration, when evaluated against human immunodeficiency virus (HIV) in vitro, significantly suppressed both the infectivity and the cytopathic effect of the virus, with 2',3'-dideoxycytidine (ddCyd) being the most potent of the series (total antiviral protection at 0.5-1.0 microM). We have compared three factors likely to be of significance in determining the pharmacological activity of these compounds, i.e., (i) their abilities to influence pool sizes of physiological deoxynucleoside-5'-triphosphates, (ii) their capacity to generate the corresponding 2',3'-dideoxynucleoside-5'-triphosphates, and (iii) the effectiveness of these nucleoside-5'-triphosphates as inhibitors of HIV reverse transcriptase. In MOLT-4 cells (a human T cell line), ddCyd was the compound most efficiently converted to its 5'-triphosphate, whereas 2',3'-dideoxyguanosine and 2',3'-dideoxythymidine were the compounds least efficiently converted, generating levels of their corresponding 5'-triphosphates less than 0.1% of that seen with ddCyd when these nucleosides were compared on an equimolar basis (5 microM). The 3'-azido analogue of 2',3'-dideoxythymidine fell intermediate between these two extremes. As inhibitors of HIV reverse transcriptase, however, all the 5'-triphosphates, with the exception of 2',3'-dideoxyinosine-5'-triphosphate, fell within a narrow range of activity (Ki, 0.10-0.26 microM), affinities some 40-60 fold greater than those of the corresponding physiological 2'-deoxynucleoside-5'-triphosphates. Significant alterations in pool sizes of physiological 2'-deoxynucleoside-5'-triphosphates were not observed at pharmacologically effective drug levels. The relative ability of 2',3'-dideoxynucleosides to generate 5'-triphosphates intracellularly thus correlates much more closely than do the other two factors examined, in capacity to block HIV replication. These studies support the conclusion that, for purposes of design of new compounds of this general class, factors influencing efficiency of nucleotide formation and degradation (e.g., membrane transport mechanisms, affinities for nucleoside kinases and for nucleotide kinases and phosphatases) may be of equal or even greater importance than differences in the relative abilities of the resultant 2',3'-dideoxynucleoside-5'-triphosphates to inhibit the viral reverse transcriptase.
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PMID:Factors determining the activity of 2',3'-dideoxynucleosides in suppressing human immunodeficiency virus in vitro. 245 90

Some 3'-blocked pyrimidine analogs were synthesized and tested as inhibitors of replication of human immunodeficiency virus (HIV) and Moloney-murine leukemia virus (MuLV). The analogs were of 3 kinds: (1) analogs of 3'-azido-3'-deoxythymidine (AZT) in which the C-5 CH3 of the base was exchanged for H (AZU) or C2H5 (AZEU); (2) 3'-fluoro-3'-deoxythymidine (FLT) and analogs thereof, in which the C-5 CH3 of the base was exchanged for H (FLU), C2H5 (FLEU) or nC3H7 (FLPU); (3) the threo analogs of AZT (AZT increases) and AZU (AZU increases). All analogs were less active inhibitors of HIV replication than AZT, except FLT, which was as active as AZT. The 3'-fluoro analogs and AZEU did not inhibit MuLV replication at non-cytotoxic concentrations. Oral administration of FLT to MuLV-infected mice result in antiviral effects only at toxic drug levels. AZU and FLU were less potent inhibitors of HIV replication than AZT or FLT, but the 2'-deoxy uridine analogs were less cytotoxic to human embryonic fibroblasts than the thymidine analogs. The 5'-triphosphates of AZU, AZT, AZEU, FLT and FLEU were tested as inhibitors of the HIV- and MuLV-reverse transcriptases. Ranking of the Ki/Km values for HIV-RT resulted in the following order of potency of the 5'-triphosphates AZT = FLT greater than AZU greater than AZEU greater than FLEU. The 5'-triphosphates of AZEU, FLT and FLEU did not inhibit the MuLV-RT, which explains, in part, the lack of effect of these analogs against MuLV replication. The threo forms (azido "up") of AZU and AZT were less active inhibitors of HIV replication than the erythro forms (azido "down"). A 15N-NMR and 1H-NMR study showed that the furanose moieties of analogs with the azido function "up" assume a conformation distinct from that of the analogs with azido "down". This is due to intramolecular stabilisation of the "N" conformer in the threo ("up") diastereomer, due to interaction of the azido functions with the nucleobase and possibly the OH group of C-5' of the furanose. As discussed, this conformation might explain the decreased biological activity of threo forms compared with the erythro forms.
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PMID:An analysis of the inhibition of replication of HIV and MuLV by some 3'-blocked pyrimidine analogs. 246 76

Oligonucleotide recognition offers a powerful chemical approach for the sequence-specific binding of double-helical DNA. In the pyrimidine-Hoogsteen model, a binding size of greater than 15 homopurine base pairs affords greater than 30 discrete sequence-specific hydrogen bonds to duplex DNA. Because pyrimidine oligonucleotides limit triple helix formation to homopurine tracts, it is desirable to determine whether oligonucleotides can be used to bind all four base pairs of DNA. A general solution would allow targeting of oligonucleotides (or their analogs) to any given sequence in the human genome. A study of 20 base triplets reveals that the triple helix can be extended from homopurine to mixed sequences. Guanine contained within a pyrimidine oligonucleotide specifically recognizes thymine.adenine base pairs in duplex DNA. Such specificity allows binding at mixed sites in DNA from simian virus 40 and human immunodeficiency virus.
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PMID:Recognition of thymine adenine.base pairs by guanine in a pyrimidine triple helix motif. 254 39

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