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: DrugBank:EXPT02079 (lysine)
58,762 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chimpanzees are susceptible to infection by divergent strains of human immunodeficiency virus type 1 (HIV-1), none of which cause clinical or immunological abnormalities. Chimpanzees were inoculated with one of four strains of HIV-1: human T-lymphotropic virus (HTLV) type IIIB, lymphadenopathy virus (LAV) type 1, HTLV type IIIRF, or an isolate from the brain of a patient with acquired immunodeficiency syndrome. Within 6 months after inoculation with the closely related strains HTLV-IIIB or LAV-1, six chimpanzees developed serum antibodies to the C-terminal half (amino acids 288-467) of the HTLV-IIIB external envelope glycoprotein gp120. Sera from five of those chimpanzees had HTLV-IIIB cell-fusion-inhibiting antibody titers greater than or equal to 20 at that time, indicating that they neutralized the infecting strain of HIV-1 in vitro. No antibodies to the carboxyl terminus of HTLV-IIIB gp120 were observed in sera of chimpanzees inoculated with HTLV-IIIRF or with the brain-tissue strain, and those sera did not neutralize HTLV-IIIB. A rabbit immunized with the C-terminal portion of gp120 acquired neutralizing antibodies that bound to four domains of the HTLV-IIIB external envelope as analyzed by reactivity to 536 overlapping nonapeptides of gp120. One of these domains in the variable region V3, with the amino acid sequence IRIQRGPGRAFVTIG (amino acids 307-321), bound to all chimpanzee sera that neutralized HTLV-IIIB but not to the serum of the HTLV-IIIRF-inoculated chimpanzee that did not neutralize HTLV-IIIB. The HTLV-IIIRF sequence at the same location, ITKGPGRVIYA, was recognized by the serum of the HTLV-IIIRF-inoculated chimpanzee but not by any sera of the HTLV-IIIB-inoculated or LAV-1-inoculated chimpanzees. The HTLV-IIIB residues RIQR and AFV and the HTLV-IIIRF residues lysine and VIYA, flanking a highly conserved beta-turn (GPGR), appear to be critical for antibody binding and subsequent type-specific virus neutralization. This neutralization epitope, putatively consisting of a loop between two cysteine residues (amino acids 296 and 331) connected by a disulfide bond, is immunodominant in HIV-1-infected chimpanzees and induces antibodies restricted to the homologous viral strain.
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PMID:Human immunodeficiency virus type 1 neutralization epitope with conserved architecture elicits early type-specific antibodies in experimentally infected chimpanzees. 245 71

Human immunodeficiency virus reverse transcriptase (HIV-RT) exhibits a strong sensitivity to pyridoxal 5'-phosphate (PLP), a substrate-binding site directed reagent for DNA polymerases (Modak, M. J. (1976) Biochemistry 15, 3620-3626). Treatment of HIV-RT with PLP followed by sodium borohydride reduction of the enzyme-PLP adduct results in irreversible inactivation of polymerase activity while RNase H activity associated with HIV-RT is minimally affected. Kinetic studies indicate that the PLP inhibition is complex. Yet one of the sites of PLP action appears to be involved in the process of dNTP binding as judged by (a) competitive mode of inhibition and (b) blockage of PLP into enzyme protein by the addition of substrate dNTP. Furthermore, this site is the only PLP reactive site which is accessible to borohydride reduction. Comparative tryptic peptide mapping of enzyme treated with PLP under a variety of conditions permitted the identification of a PLP reactive site containing peptide. Furthermore, reactivity of this site was also blocked by inclusion of substrate dNTP and appropriate template-primer. The amino acid composition and sequence analysis of this peptide showed that a lysine residue present at position 263 in the primary amino acid sequence of HIV-RT is the site of PLP reactivity. We therefore conclude that lysine 263 serves as an important part of the dNTP-binding domain in HIV-RT.
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PMID:Substrate binding in human immunodeficiency virus reverse transcriptase. An analysis of pyridoxal 5'-phosphate sensitivity and identification of lysine 263 in the substrate-binding domain. 247 Jul 47

The envelope glycoproteins of the human immunodeficiency virus (HIV) type 1 are synthesized as a precursor molecule, gp160, which is cleaved to generate the two mature envelope glycoproteins, gp120 and gp41. The cleavage reaction, which is mediated by a host protease, occurs at a sequence highly conserved in retroviral envelope glycoprotein precursors. We have investigated the sequence requirements for this cleavage reaction by introducing four single-amino-acid changes into the glutamic acid-lysine-arginine sequence immediately amino terminal to the site of cleavage. We have also examined the effects of these mutations on the syncytium formation induced by HIV envelope glycoproteins. Our results indicate that a glutamic acid to glycine change at gp120 amino acid 516, a lysine to isoleucine change at amino acid 517, and an arginine to lysine change at amino acid 518 affect neither gp160 cleavage nor syncytium formation. The results obtained with the arginine to lysine change at amino acid 518 differ significantly from the results obtained with the same mutation at the envelope precursor cleavage site of a murine leukemia virus (E. O. Freed, and R. Risser, J. Virol. 61:2852-2856, 1987). An arginine to threonine mutation at gp120 amino acid 518, the terminal residue of gp120, abolishes both gp160 cleavage and syncytium formation. These findings demonstrate that despite its highly conserved nature, the basic pair of amino acids at the site of gp160 cleavage is not absolutely required for proper envelope glycoprotein processing. This report also supports the idea that cleavage of gp160 is required for activation of the HIV envelope fusion function.
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PMID:Mutational analysis of the cleavage sequence of the human immunodeficiency virus type 1 envelope glycoprotein precursor gp160. 267

The ability of poly(L-lysine)-conjugated and methylphosphonate-modified synthetic human immunodeficiency virus type 1 (HIV-1) antisense oligodeoxyribonucleotides to protect susceptible host cells from the cytopathic effects of HIV-1 infection was studied. The abundance of viral antigens in oligomer-treated cultures indicated that the oligomers did not significantly affect viral infectivity. Similarly, no significant effects on relative viral RNA accumulation were apparent. The presence of poly(L-lysine)-modified oligomer complementary to the HIV-1 splice donor site resulted in a significant reduction in the production of viral structural proteins and virus titre in infected cultures. In addition, these cells were protected from HIV-1-mediated cytopathic effects while the other cultures rapidly succumbed to the cytotoxic effects of HIV-1 infection. The presence of poly(L-lysine)-conjugated oligomer resulted in the establishment of a persistent HIV-1 infection characterized by a highly productive virus infection in the absence of cell death while treatment of persistently infected cells with phorbol ester resulted in renewed cytopathicity. These results demonstrate the ability of synthetic antisense oligonucleotides to protect susceptible host cells from the cytopathic effects of HIV-1 infection.
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PMID:Inhibition of human immunodeficiency virus type 1-mediated cytopathic effects by poly(L-lysine)-conjugated synthetic antisense oligodeoxyribonucleotides. 279 75

Single nucleotide alterations were introduced into an infectious clone of human immunodeficiency virus type 1 to create a series of missense mutants in the tat coding region. Although mutations in a proline-rich region and a basic lysine-arginine-rich region resulted in wild-type phenotypes, five of six mutations in a cysteine-rich domain completely abolished tat activity and virus replication. One cysteine mutant retained tat activity but was negative for virus expression. Surprisingly, this mutant could not be complemented by tat, and virus expression was restored only by cotransfection with a plasmid expressing the rev gene. Another mutant with an alteration toward the C-terminal region showed significantly reduced tat activity and required complementation by a combination of tat and rev for virus replication. Further analysis revealed that a previously unrecognized splice acceptor site within this region, apparently used to generate the rev mRNA, had been altered. We provide evidence suggesting that tat and rev proteins are encoded by distinct mRNA species.
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PMID:Missense mutations in an infectious human immunodeficiency viral genome: functional mapping of tat and identification of the rev splice acceptor. 319 21

A 96-well microtiter infection assay for the human immunodeficiency virus (HIV) is described. The assay utilizes human T-cell lymphotropic virus type I-immortalized MT-2 cells as targets for infection and requires only 4 to 5 days for completion. Cytolysis was quantitated by vital dye uptake of poly-L-lysine-adhered cells as an endpoint for infection. The assay's efficacy was proven by the sensitive and accurate assessment of several known anti-HIV agents including two inhibitors of reverse transcription (3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine), three biological response modifiers (recombinant interferons alpha and beta and mismatched double-stranded RNA), a direct inactivator of HIV virions (amphotericin B), and neutralizing antibodies from two HIV-positive human subjects. Evaluation of data was facilitated by computer-assisted analysis. This assay provides a means for rapid, sensitive, and inexpensive large-scale in vitro testing of potential anti-HIV therapeutic regimens and quantitation of HIV-neutralizing antibody titers.
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PMID:Evaluation of antiviral drugs and neutralizing antibodies to human immunodeficiency virus by a rapid and sensitive microtiter infection assay. 342 47

Stimulation of resistance induced by muramyl dipeptide (MDP) and its analog, N alpha-MDP-N epsilon-stearoyl-L-lysine [MDP-Lys(L18)], was examined in experimental salmonellosis in CBA/N defective mice with X-linked immunodeficiency to virulent Salmonella enteritidis no. 11. An injection of either MDP or MDP-Lys(L18) did not induce any effective protection, but repeated injections of MDP-Lys(L18) (100 micrograms per mouse per day for 3 days consecutively) to the mice before bacterial challenge gave some protection. Multiple injections with MDPs once a day for several days consecutively strongly increased bactericidal capacity in the peritoneal cavities and spleens of the mice. Moreover, previous injection of the MDPs could elevate the phagocytic function of the reticuloendothelial system in the defective mice. These results indicate that nonspecific resistance of CBA/N defective mice to salmonella infection can be improved by previous administrations of MDPs.
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PMID:Augmentation of protective and antibacterial activity induced by muramyl dipeptides in CBA/N defective mice with X-linked immunodeficiency for Salmonella enteritidis infection. 637 98

A valine to isoleucine substitution at position 322 within variable region 3 (V3) of envelope of simian immunodeficiency virus was previously shown to compensate for an inactivating valine to glycine mutation at position 448 in constant region 4 (C4) (Morrison et al., Virology 195, 167-174, 1993). Cloned DNA fragments with inactivating C4 mutations were combined with complex mixtures of mutant V3 sequences, and full length genomes were transfected into COS-1 cells. By cocultivating transfected cells with CEM x 174 cells, we were able to identify two additional compensatory V3-C4 combinations. Changing 334 proline to leucine compensated for an inactivating 428 asparagine to lysine mutation and changing 324 isoleucine to leucine compensated for an inactivating 448 valine to glycine mutation. The double mutants replicated efficiently in CEM x 174 cells, rhesus monkey peripheral blood mononuclear cells, and the continuously growing rhesus monkey T cell line 221. Surprisingly, the 324 I-->L and 33 P-->L mutations by themselves impaired SIVmac239 wild-type replication in CEM x 174 cells. These results confirm the cooperation between V3 and C4 sequences and they define additional specific residues participating in this cooperation.
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PMID:Identification of V3 mutations that can compensate for inactivating mutations in C4 of simian immunodeficiency virus. 748 61

A human immunodeficiency virus type 1 variant resistant to zalcitabine (2',3'-dideoxycytidine [ddC]) was selected by sequential passage in the presence of increasing concentrations of ddC in peripheral blood mononuclear cell cultures. A mutation causing a lysine-to-arginine substitution was noted in reverse transcriptase (RT) codon 65 of this ddC-selected virus. A cloned mutant virus with this codon 65 mutation was constructed by using a novel PCR approach for site-directed mutagenesis. Characterization of this virus confirmed that the RT Lys-65-->Arg substitution was necessary and sufficient for a fourfold increase in the ddC 50% inhibitory concentration, as well as for resistance to didanosine (2',3'-dideoxyinosine [ddI]). Lys-65-->Arg and virus resistance to ddC and ddI also developed during therapy in isolates from one ddC-treated patient and two ddI-treated patients. Recombinant-expressed codon 65 mutant RT enzyme was resistant to ddCTP and ddATP in cell-free polymerase assays. Results of mutant enzyme studies are consistent with Lys-65-->Arg leading to changes in binding of the triphosphate forms of these nucleoside analogs to the RT. These data have implications for future studies of ddC resistance, particularly those aimed at defining its clinical relevance.
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PMID:Resistance to 2',3'-dideoxycytidine conferred by a mutation in codon 65 of the human immunodeficiency virus type 1 reverse transcriptase. 751 56

The structural proteins of human immunodeficiency virus type 1, for example, Gag and Env, are encoded by unspliced and incompletely spliced viral transcripts. The expression of these mRNAs in the cytoplasm, along with their commensurate translation, is absolutely dependent on the virally encoded Rev trans activator. Previous studies have demonstrated that Rev binds directly to its substrate mRNAs via an arginine-rich element that also serves as its nuclear localization sequence. In an attempt to define the specific amino acid residues that are important for in vivo activity, we have constructed a series of missense mutations that scan across this region. Our data demonstrate that all eight arginine residues within this element can, individually, be substituted for either leucine or lysine with no apparent loss of function. Importantly, these findings suggest that no single amino acid within the arginine-rich domain of Rev is, by itself, essential for activity and that considerable functional redundancy is therefore likely to exist within this region. Interestingly, one mutant in which a tryptophan had been substituted for a serine failed to accumulate exclusively in the nucleus but still bound RNA in a manner that was indistinguishable from that of the wild-type protein. This observation indicates that features of the arginine-rich region that are additional to those required for RNA binding are important for Rev's correct accumulation in the nucleus.
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PMID:Scanning mutagenesis of the arginine-rich region of the human immunodeficiency virus type 1 Rev trans activator. 752 98


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