Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recognition and cleavage of tRNAPhe and the TAR RNA of HIV-1 by metallopeptides of the general form Ni(II).Xaa-Gly-His (where Xaa is Gly, Lys, or Arg) were investigated. The results of RNA cleavage analyses suggest that KHSO5- or magnesium monoperoxyphthalate-activated metallopeptides (1) induce nucleobase damage which requires aniline acetate for complete RNA strand scission and (2) selectively target the loops of stem-loop structures of the above-named substrates. In targeting RNA loop regions, the metallopeptides may be sensitive to intraloop structural features, including the overall structural environment of the loop itself and possibly the presence of intraloop hydrogen bonding. Overall, these results suggest that the metallopeptides interact selectively within a loop, in a fashion reminiscent of many RNA binding proteins, instead of targeting RNA single-stranded character alone. These observations further suggest a possible metallopeptide-based strategy for the molecular recognition of native RNA structures and insight with regard to the general features available for ligand binding site discrimination.
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PMID:Selective recognition and cleavage of RNA loop structures by Ni(II).Xaa-Gly-His metallopeptides. 972 23

A study on the use of derivatized carbohydrates as C2-symmetric HIV-1 protease inhibitors has been undertaken. L-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C2-symmetric products based on C-terminal duplication. Potent HIV protease inhibitors, 28 Ki = 0.4 nM and 43 Ki = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be prepared in just three chemical steps from commercially available materials. A remarkable increase in potency going from IC50 = 5000 nM (23) to IC50 = 15 nM (28) was observed upon exchanging -COOMe for -CONHMe in the inhibitor, resulting in the net addition of one hydrogen bond interaction between each of the two -NH- groups and the HIV protease backbone (Gly 48/148). The X-ray crystal structures of 43 and of 48 have been determined (Figures 5 and 6), revealing the binding mode of these inhibitors which will aid further design.
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PMID:Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of L-mannaric acid as a peptidomimetic scaffold. 974 53

Like the CCR5 chemokine receptors of humans and rhesus macaques, the very homologous (approximately 98-99% identical) CCR5 of African green monkeys (AGMs) avidly binds beta-chemokines and functions as a coreceptor for simian immunodeficiency viruses. However, AGM CCR5 is a weak coreceptor for tested macrophage-tropic (R5) isolates of human immunodeficiency virus type 1 (HIV-1). Correspondingly, gp120 envelope glycoproteins derived from R5 isolates of HIV-1 bind poorly to AGM CCR5. We focused on a unique extracellular amino acid substitution at the juncture of transmembrane helix 4 (TM4) and extracellular loop 2 (ECL2) (Arg for Gly at amino acid 163 (G163R)) as the likely source of the weak R5 gp120 binding and HIV-1 coreceptor properties of AGM CCR5. Accordingly, a G163R mutant of human CCR5 was severely attenuated in its ability to bind R5 gp120s and to mediate infection by R5 HIV-1 isolates. Conversely, the R163G mutant of AGM CCR5 was substantially strengthened as a coreceptor for HIV-1 and had improved R5 gp120 binding affinity relative to the wild-type AGM CCR5. These substitutions at amino acid position 163 had no effect on chemokine binding or signal transduction, suggesting the absence of structural alterations. The 2D7 monoclonal antibody has been reported to bind to ECL2 and to block HIV-1 binding and infection. Whereas 2D7 antibody binding to CCR5 was unaffected by the G163R mutation, it was prevented by a conservative ECL2 substitution (K171R), shared between rhesus and AGM CCR5s. Thus, it appears that the 2D7 antibody binds to an epitope that includes Lys-171 and may block HIV-1 infection mediated by CCR5 by occluding an HIV-1-binding site in the vicinity of Gly-163. In summary, our results identify a site for gp120 interaction that is critical for R5 isolates of HIV-1 in the central core of human CCR5, and we propose that this site collaborates with a previously identified region in the CCR5 amino terminus to enable gp120 binding and HIV-1 infections.
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PMID:A critical site in the core of the CCR5 chemokine receptor required for binding and infectivity of human immunodeficiency virus type 1. 989 Sep 44

The serine protease CD26/dipeptidyl-peptidase IV (CD26/DPP IV) and chemokines are known key players in immunological processes. Surprisingly, CD26/DPP IV not only removed the expected Gly1-Pro2 dipeptide from the NH2 terminus of macrophage-derived chemokine (MDC) but subsequently also the Tyr3-Gly4 dipeptide, generating MDC(5-69). This second cleavage after a Gly residue demonstrated that the substrate specificity of this protease is less restricted than anticipated. The unusual processing of MDC by CD26/DPP IV was confirmed on the synthetic peptides GPYGANMED (MDC(1-9)) and YGANMED (MDC(3-9)). Compared with intact MDC(1-69), CD26/DPP IV-processed MDC(5-69) had reduced chemotactic activity on lymphocytes and monocyte-derived dendritic cells, showed impaired mobilization of intracellular Ca2+ through CC chemokine receptor 4 (CCR4), and was unable to desensitize for MDC-induced Ca2+-responses in CCR4 transfectants. However, MDC(5-69) remained equally chemotactic as intact MDC(1-69) on monocytes. In contrast to the reduced binding to lymphocytes and CCR4 transfectants, MDC(5-69) retained its binding properties to monocytes and its anti-HIV-1 activity. Thus, NH2-terminal truncation of MDC by CD26/DPP IV has profound biological consequences and may be an important regulatory mechanism during the migration of Th2 lymphocytes and dendritic cells to germinal centers and to sites of inflammation.
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PMID:Truncation of macrophage-derived chemokine by CD26/ dipeptidyl-peptidase IV beyond its predicted cleavage site affects chemotactic activity and CC chemokine receptor 4 interaction. 993 89

Solid-state NMR measurements have been carried out on frozen solutions of the complex of a 24-residue peptide derived from the third variable (V3) loop of the HIV-1 envelope glycoprotein gp120 bound to the Fab fragment of an anti-gp120 antibody. The measurements place strong constraints on the conformation of the conserved central GPGR motif of the V3 loop in the antibody-bound state. In combination with earlier crystal structures of V3 peptide-antibody complexes and existing data on the cross-reactivity of the antibodies, the solid-state NMR measurements suggest that the Gly-Pro-Gly-Arg (GPGR) motif adopts an antibody-dependent conformation in the bound state and may be conformationally heterogeneous in unbound, full-length gp120. These measurements are the first application of solid-state NMR methods in a structural study of a peptide-protein complex.
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PMID:Solid-state NMR evidence for an antibody-dependent conformation of the V3 loop of HIV-1 gp120. 1004 25

The model of spatial structure for the principal neutralizing determinant (PND) of the HIV-1 envelope protein gp120 is proposed in terms of two-dimensional nuclear Overhauser effect (NOE) spectroscopy data. To build the model, the NMR-based theoretical conformational analysis of synthetic PND peptides of length 40, 24, and 12 residues is carried out. The modeling of the molecular spatial structures is performed by a new approach to research of conformationally mobile peptides using the algorithms of the restrained molecular mechanics method developed earlier. The following major conclusions are made based on the analysis of the simulated peptide conformations: i) there is not unique PND structure in solution, ii) there are seven different PND structures each of which agrees with the experimental data and stereochemical criteria used in computing its spatial model, iii) the PND is characterized by irregular conformation containing a number of reverse turns, iv) all of the selected conformations are conserved in the Gly-Pro-Gly-Arg-Ala-Phe stretch, the most probable viral immunodominant epitope. These data allow to suppose that binding properties of this site are determined by the structural motif which forms the conformation of a double beta-turn and appears common for all hexapeptide structures.
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PMID:Global and local structural properties of the principal neutralizing determinant of the HIV-1 envelope protein gp120. 1021 60

A convenient 'on line' solid-phase synthesis of oligonucleotides conjugated at the 3'-end with peptides by means of a polymeric support linking the first nucleoside via the base has been developed. A 17-mer designed for antisense experiments against HIV-1, linking at the 3'-terminus the tripeptide Gly-Gly-His, was prepared in good yields and characterized by MALDI-TOF mass spectrometry.
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PMID:A new solid-phase synthesis of oligonucleotides 3'-conjugated with peptides. 1021 34

Endogneous delta and kappa opioid peptides possess a variety of immunomodulatory properties, and kappa-opioid receptor ligands recently were shown to suppress the expression of human immunodeficiency virus type 1 (HIV-1) in microglial cells, the resident macrophages of the brain. To determine whether the newly discovered endogenous mu-opioid receptor ligands endomorphin-1 and -2 would affect HIV-1 replication, these peptides were added to acutely infected brain cell cultures. Endomorphin-1 potentiated viral expression, in a bell-shaped dose-response manner with maximal enhancement approximately equal to 35% at 10(-10) M, in both mixed glial/neuronal cell and purified microglial cell cultures. Endomorphin-1's amplifying effect was blocked by pretreatment of brain cells with either the mu-opioid receptor selective antagonist beta-funaltrexamine or the G protein inhibitor pertussis toxin. However, the classical mu receptor agonists morphine and DAMGO (Tyr-d-Ala-Gly-N-Me-Phe-Gly-ol) had no effect on viral expression or on endomorphin-1's amplifying effect. Taken together, these findings suggest that in this in vitro model of HIV-1 brain infection, endomorphin-1 potentiates viral expression via activation of an atypical mu-selective opioid receptor. They also provide evidence, for the first time, that an endogenous mu-opioid peptide has neuroimmunomodulatory activity.
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PMID:Endomorphin-1 potentiates HIV-1 expression in human brain cell cultures: implication of an atypical mu-opioid receptor. 1021 68

An immunogenic sequence from the V3 loop of the MN isolate of human immunodeficiency virus type 1 (HIV-1), His-Ile-Gly-Pro-Gly-Arg-Ala-Phe, was transplanted onto a surface loop of the VP2 capsid protein of human rhinovirus 14. To optimize for virus viability and immunogenicity of the transplanted sequence, the HIV sequence was flanked by (1) a cysteine residue that could form a disulfide bond and (2) randomized amino acids (in either of two arrangements) to generate numerous presentations of the Cys-Cys loop. The location for engineering in VP2 was chosen by searching the geometries of disulfide-bound loops in known protein structures. A model for the structure of the transplanted V3 loop sequence was developed using molecular dynamics and energy minimization calculations. Proteolytic digestion with and without reducing agent demonstrated the presence of the disulfide bond in the chimeric virus examined. Monoclonal and polyclonal antibodies directed against the V3 region of the HIV-1MN strain potently neutralized two chimeric viruses. Guinea pig antisera against two chimeric viruses were able to neutralize HIV-1MN and HIV-1ALA-1 in cell culture. The ability of chimeric viruses to elicit antibodies capable of neutralizing the source of the transplanted sequence could be favorable for vaccine development.
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PMID:A disulfide-bound HIV-1 V3 loop sequence on the surface of human rhinovirus 14 induces neutralizing responses against HIV-1. 1022 39

A model of spatial structure of the synthetic peptide rp142 (24 amino acid residues) containing the immunodominant epitope of the HIV-1 protein gp120 in the region Gly-10-Phe-15 was constructed by the method of "constrained" molecular mechanics, which uses the algorithms of theoretical conformational analysis, based on NMR spectroscopy data. A comparative analysis of calculated conformations revealed that the spatial structure of rp142 in solution can be described by a family of conformations to which nine different structural clusters involving the sets of topologically close conformers correspond. It is shown that the main chain of the peptide forms irregular but "structured" conformations in which the main portion of amino acid residues is incorporated into beta-turns and helix-like fragments, while Pro-11 and Gly-12 form in some structures inverse gamma-turns, which rarely occur in protein-peptide molecules. It was found that the spatial packing of the Gly-10-Phe-15 hexapeptide in different clusters is realized at different internal rotation angles, to which topologically close structures correspond. It is assumed that this invariant structural element describes the "conformation of complex formation" that is complementary to the antigen-binding center of antibodies and is responsible for their binding to the peptide.
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PMID:[Spatial structure of the rp142 peptide containing the immunodominant epitope of the HIV-1 gp120 protein. A theoretical study]. 1033 May 79


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