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 dipeptides N-carbomethoxycarbonyl-prolyl-phenylalanyl-benzyl esters (CPFs) play a significant role in the prevention of HIV-1 virus infection by interacting with the glycoprotein gp120, one of the envelope proteins of the HIV-1 virus. Of the four possible isomers of CPF, (L-pro-L-phe), (L-pro-D-phe), (D-pro-L-phe) and (D-pro-D-phe), herein denoted LL etc., the crystal structures of LL, stereoisomeric LD and the racemic mixture of LD/DL have been determined. All three peptides crystallize in the orthorhombic system and they all have similar cell dimensions: (i) LL, P2(1)2(1)2(1), a = 13.699(2), b = 25.893(5), c = 6.155(1) A, Z = 4, Dcale = 1.333 g cm-3, R = 0.070 for 1247 observed reflections; (ii) LD, P2(1)2(1)2(1), a = 11.663(2), b = 26.557(2), c = 7.281(1) A, Z = 4, Dcalc = 1.290 g cm-3, R = 0.054 for 1918 observed reflections; (iii) LD/DL, Pbc2(1), a = 11.953(2), b = 24.208(8), c = 7.782(2) A, Z = 4, Dcalc = 1.292 g cm-3, R = 0.080 for 894 observed reflections. Both the enantiomeric LD and the LD in racemic LD/DL have a similar conformation, an extended peptide chain with phi 1 = -76, -73 degrees; psi 1 = 160, 158 degrees, psi 2 = 123, 131 degrees and psi 2 = -172, -167 degrees, while peptide LL adopts a bent conformation at the Phe residue, phi 1 = -69 degrees, psi 1 = 158 degrees, phi 2 = -60 degrees and psi 2 = -34 degrees.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular structures of CPF-dipeptides, inhibitors for the binding of CD4 with gp120. 792 82

The glycosphingolipid galactosylceramide (GalCer), which binds gp120 with high affinity and specificity, is a potential alternative receptor for human immunodeficiency virus type 1 (HIV-1) in some CD4-negative neural and epithelial human cells, including the human colonic epithelial cell line HT-29. In the present study, we demonstrate that synthetic multibranched peptides derived from the consensus sequence of the HIV-1 V3 loop block HIV-1 infection in HT-29 cells. The most active peptide was an eight-branched multimer of the motif Gly-Pro-Gly-Arg-Ala-Phe which at a concentration of 1.8 microM induced a 50% inhibition of HIV-1 infection in competition experiments. This peptide was not toxic to HT-29 cells, and preincubation with HIV-1 did not affect viral infectivity, indicating that the antiviral activity was not due to a nonspecific virucidal effect. Using a high-performance thin-layer chromatography binding assay, we found that multibranched V3 peptides recognized GalCer and inhibited binding of recombinant gp120 to the glycosphingolipid. In addition, these peptides abolished the binding of an anti-GalCer monoclonal antibody to GalCer on the surface of live HT-29 cells. These data provide additional evidence that the V3 loop is involved in the binding of gp120 to the GalCer receptor and show that multibranched V3 peptides are potent inhibitors of the GalCer-dependent pathway of HIV-1 infection in CD4-negative mucosal epithelial cells.
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PMID:Synthetic multimeric peptides derived from the principal neutralization domain (V3 loop) of human immunodeficiency virus type 1 (HIV-1) gp120 bind to galactosylceramide and block HIV-1 infection in a human CD4-negative mucosal epithelial cell line. 798 25

A new type of pseudopeptide isostere exampled by Phe psi[CH2CH(OH)]Phe was synthesized from phenylalanine. The HIV protease inhibitory activity (IC50) of Noa-His-Phe psi[CH2CH(OH)]Phe-Ile-Amp was 0.8 pmol.L-1.
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PMID:Synthesis of a new hydroxyethylene dipeptide isostere Phe psi [CH2CH (OH)]Phe as HIV-1 protease inhibitor. 801 81

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

The high binding affinity and specificity of antibodies for a great variety of ligands has been widely exploited in structure-activity relationship studies of biomolecules and more recently in the development of new catalysts for several chemical reactions. It is assumed that antibodies generated against haptenic protease inhibitors would recognize both these haptens and the substrate of the model proteolytic reaction. We have produced antibodies against HIV PRp12 aspartyl protease substrate analogues, chemically modified at the scissile bond, Phe-Pro. Identical chemical modifications have been reported for related HIV protease inhibitors. We finally selected an anti-hapten monoclonal antibody that specifically recognized the substrate and those haptens with both the phenylalanyl side chain and the prolyl pyrrolidine ring. This selectivity of recognition suggests that such an antibody might mimic the catalytic site of the model protease.
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PMID:Characterization of a monoclonal antibody produced in an attempt to mimic the active site of HIV aspartyl protease using haptens based on inhibitor models. 804 48

The purposes of this study were to map the targets for neutralizing Abs in the HIV-2 glycoproteins with particular emphasis on the role of the V3 region. Sera obtained from guinea pig immunized with peptides representing five immunogenic regions of the envelope proteins were used in cross-neutralization experiments with nine HIV-2 isolates. Broad cross-neutralizing activity was elicited by immunization with two peptides representing the central and COOH-terminal portions of the HIV-2 V3 loop. Murine mAbs were established from animals immunized with two corresponding overlapping peptides. Six mAbs showed neutralizing activity against the homologous virus isolate SBL-6669. Peptide absorption experiments were performed to define the target regions for human neutralizing Abs in the HIV-2 envelope glycoproteins. A significant blocking of neutralizing activity of five HIV-2 Ab-positive sera was seen in the presence of two peptides corresponding to the V3 region. Two overlapping deletion sets of peptides, representing amino acids Ser311 and Arg337, were used to identify the role of individual HIV-2 V3 amino acids in the binding of polyclonal and mAbs. Two distinct antigenic sites were identified in this region, the first corresponding to a region including the conserved motif Phe-His-Ser (amino acid 315-317) and the second in proximity of the COOH-terminal cysteine Trp-Cys-Arg (amino acid 329-331). Potentially these two sites can interact to represent a single discontinuous antigenic site. Taken together, these results indicate that V3 is an important neutralizing domain of HIV-2.
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PMID:Two neutralizing domains in the V3 region in the envelope glycoprotein gp125 of HIV type 2. 812 Mar 99

A 15-17 nucleotide sequence from the gag-pol ribosome frameshift site of HIV-1 directs analogous ribosomal frameshifting in Escherichia coli. Limitation for leucine, which is encoded precisely at the frameshift site, dramatically increased the frequency of leftward frameshifting. Limitation for phenylalanine or arginine, which are encoded just before and just after the frameshift, did not significantly affect frameshifting. Protein sequence analysis demonstrated the occurrence of two closely related frameshift mechanisms. In the first, ribosomes appear to bind leucyl-tRNA at the frameshift site and then slip leftward. This is the 'simultaneous slippage' mechanism. In the second, ribosomes appear to slip before binding aminoacyl-tRNA, and then bind phenylalanyl-tRNA, which is encoded in the left-shifted reading frame. This mechanism is identical to the 'overlapping reading' we have demonstrated at other bacterial frameshift sites. The HIV-1 sequence is prone to frame-shifting by both mechanisms in E. coli.
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PMID:The function of a ribosomal frameshifting signal from human immunodeficiency virus-1 in Escherichia coli. 817 Mar 92

Antinociceptive activity of seven pentapeptide fragments of human adenovirus type 2 (Ad2) virion proteins: Thr-Val-Pro-Pro-Arg (1), Thr-Arg-Pro-Pro-Arg (2), Thr-Gly-Pro-Pro-Thr (3), Pro-Arg-Pro-Pro-Thr (4), Phe-Val-Pro-Pro-Arg (5), Ala-Arg-Pro-Pro-Ala (6), Tyr-Gly-Pro-Pro-Lys (7)--analogs of known tuftsin inhibitor Thr-Lys-Pro-Pro-Arg, was measured by hot-plate procedure. Also two tuftsin-like fragments of epitopes of HIV-1 and HIV-2: Thr-Lys-Ala-Lys (8), Thr-Lys-Glu-Lys (9), and tuftsin analog Thr-Lys-Asp-Lys (10) were tested. In the control experiments the effects of tuftsin and pentapeptide tuftsin inhibitor were also studied. The peptides 2, 4 and 5 were found to produce very strong analgesia after the icv injection. It was observed that pretreatment with peptide 8 remarkably diminished the antinociceptive effect induced by tuftsin.
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PMID:The analgesic activity of some tuftsin- and tuftsin inhibitor-like fragments of the viral coat proteins. 822 Jun 60

Using the process of "antibody antigenization," we engineered two antibody molecules carrying in the third complementarity-determining region of the heavy chain variable domain a 7-mer or a 15-mer peptide epitope of the first extracellular domain (D1) of human CD4 receptor--namely, Ser-Phe-Leu-Thr-Lys-Gly-Pro-Ser (SFLTKGPS; positions 42 through 49) and Gly-Ser-Phe-Leu-Thr-Lys-Gly-Pro-Ser-Lys-Leu-Asn-Asp-Arg-Ala (GSFLTKGPSKLNDRA; positions 41 through 55). These amino acid sequences are contained in the consensus binding site for the human immunodeficiency virus (HIV) on CD4 receptor. Both antigenized antibodies (AgAbs) bound recombinant gp120 and were recognized by a prototype monoclonal antibody to CD4 whose binding site is within amino acid residues 41-55. AgAbs were then used as immunogens in rabbits and mice to elicit a humoral response against CD4. Only the AgAb carrying the sequence 41GSFLTKGPSKLN-DRA55 induced a response against CD4. The induced antibodies showed specificity for the amino acid sequence of CD4 engineered in the AgAb molecule, were able to inhibit the formation of syncytia between human CD4+ T cells MOLT-3 and 8E5 (T cells that are constitutively infected with HIV), and stained human CD4+ CEM T cells. Four murine monoclonal antibodies were used to analyze the relationship between syncytia inhibition and CD4 binding at the single antibody level, and indicated that recognition of native CD4 is not an absolute requirement for inhibition of syncytia. This study demonstrates that antigenized antibodies can be used as immunogens to elicit site-specific and biologically active immunity to CD4. The importance of this approach as a general way to induce anti-receptor immunity and as a possible new measure to immunointervention in HIV infection is discussed.
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PMID:Active immunity against the CD4 receptor by using an antibody antigenized with residues 41-55 of the first extracellular domain. 826 9

We present the application of free energy perturbation theory/molecular dynamics to predict the consequence of replacing each of the seven peptide bonds in the potent HIV protease inhibitor JG365: ACE (acetyl)-Ser-Leu-Asn-HEA (hydroxyethylamine analog of Phe-Pro)-Ile-Val-NME (N-methyl) by ethylene or fluoroethylene isosteres. Replacing two of these bonds may well lead to significantly tighter binding; replacing two others is predicted to significantly diminish the binding affinity. Also, for three of the peptide bonds fluoroethylene replacements could lead to increased binding of free energies of the inhibitors. Our results should be considered as predictive since there are, as yet, no experimental results on such peptide replacements as enzyme inhibitors.
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PMID:Peptide mimetics as enzyme inhibitors: use of free energy perturbation calculations to evaluate isosteric replacement for amide bonds in a potent HIV protease inhibitor. 837 26


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