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

The structure-activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing alpha-hydroxy-beta-amino acids is discussed. We demonstrated that substituent groups on the P1 aromatic rings of the inhibitors exert significant influence on their biological activity. Inhibitors bearing an alkyl or a fluorine atom at the meta and para position on their P1 benzene ring were found to be good inhibitors. We also discovered that the substitution positions of the P2 benzamides were crucial for good antiviral potency. In this study, inhibitor 48 was the most potent [IC90 (CEM/HIV-1 IIIB) 27 nM] and showed good pharmacokinetics in rats.
 ...
PMID:Structure-activity relationship of HIV-1 protease inhibitors containing alpha-hydroxy-beta-amino acids. Detailed study of P1 site. 1053 Sep 56

A series of 6-aminoquinolone compounds were evaluated for their in vitro activity against human immunodeficiency virus type 1 (HIV-1). Compound 12a, bearing a methyl substituent at the N-1 position and a 4-(2-pyridyl)-1-piperazine moiety at the C-7 position, was the most active in inhibiting HIV-1 replication on de novo infected C8166 human lymphoblastoid cell lines. The 12a EC(50) value was 0.1 microM, a 7-20-fold lower concentration relative to that for compounds 8a and 7a containing a cyclopropyl and tert-butyl substituent at the N-1 position, respectively. When the C-6 amino group was replaced with a fluorine atom, a decreased antiviral effect was observed. The observed effects are selective, since potency is substantially reduced when testing the compounds against the herpes simplex virus type 1 (HSV-1). Active quinolone derivatives very efficiently interact with TAR RNA, which suggests a nucleic acid-targeted mechanism of action.
 ...
PMID:6-Aminoquinolones as new potential anti-HIV agents. 1102 Feb 96

The in-vitro metabolism of GW420867X ((S)-2-ethyl-7-fluoro-3-oxo-3, 4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester), a quinoxaline drug for the potential treatment of HIV, has been studied with singly expressed human cytochromes P450 (CYP 450). No biotransformation of [14C]GW420867X was evident in the presence of any of the CYP 450 isoforms, with the exception of CYP 450 1A2, where a single metabolite was observed in the HPLC radiochromatograms of enzyme incubations with the test compound. The structure of this metabolite was determined by nuclear magnetic resonance spectroscopy and mass spectrometry, and was shown to correspond to the replacement of the aromatic fluorine of GW420867X with a hydroxyl group. Thus, it appeared that CYP 450 1A2 catalysed the specific defluorination of GW420867X, presumably during formation of an arene oxide intermediate during aromatic hydroxylation.
 ...
PMID:Formation of a defluorinated metabolite of a quinoxaline antiviral drug catalysed by human cytochrome P450 1A2. 1129 57

[reaction: see text] L-2'-Fluoro-4'-thio-2',3'-unsaturated cytidine 11 was synthesized from (R)-2-fluorobutenolide 2, which was prepared from 2,3-O-isopropylidene-L-glyceraldehyde 1. The synthesized compound 11 shows potent antiviral activity against HIV-1.
 ...
PMID:Synthesis and potent anti-HIV activity of L-2',3'-didehydro-2',3'-dideoxy-2'-fluoro-4'-thiocytidine. 1179 76

Binding of Mg2+, Ca2+ and Co(NH3)6(3+) ions to the HIV-1 TAR RNA in solution was analysed by 19F NMR spectroscopy, metal ion-induced RNA cleavages and Brownian dynamics (BD) simulations. Chemically synthesised 29mer oligoribonucleotides of the TAR sequence labelled with 5-fluorouridine (FU) were used for 19F NMR-monitored metal ion titration. The chemical shift changes of fluorine resonances FU-23, FU-25 and FU-40 upon titration with Mg2+ and Ca2+ ions indicated specific, although weak, binding at the bulge region with the dissociation constants (K(d)) of 0.9 +/- 0.6 and 2.7 +/- 1.7 mM, respectively. Argininamide, inducing largest (19)F chemical shifts changes at FU-23, was used as a reference ligand (K(d) = 0.3 +/- 0.1 mM). In the Pb2+-induced TAR RNA cleavage experiment, strong and selective cleavage of the C24-U25 phosphodiester bond was observed, while Mg2+ and Ca2+ induced cuts at all 3-nt residues of the bulge. The inhibition of Pb2+-specific TAR cleavage by di- and trivalent metal ions revealed a binding specificity [in the order Co(NH3)6(3+) > Mg2+ > Ca2+] at the bulge site. A BD simulation search of potential magnesium ion sites within the NMR structure of HIV-1 TAR RNA was conducted on a set of 20 conformers (PDB code 1ANR). For most cases, the bulge region was targeted by magnesium cations.
 ...
PMID:The bulge region of HIV-1 TAR RNA binds metal ions in solution. 1236 3

RNA interference (RNAi) is an ancient antiviral response that processes dsRNA and associates it into a nuclease complex that identifies RNA with sequence homology and specifically cleaves it. We demonstrate that RNAi mediated by 21-bp dsRNA specifically inhibits HIV-1 infection of permanent cell lines and primary CD4(+) T cells. Inhibition of HIV replication was measured by p24 Gag protein content in supernatant, Northern blot analysis, and DNA PCR for products of reverse transcription. The inhibition occurred at two points in the viral life cycle, after fusion and before reverse transcription and during transcription of viral RNA from integrated provirus. Treatment of HIV-infected activated CD4(+) T cells with a fluorine-derivatized siRNA that is resistant to RNase A yielded similar inhibition of HIV infection. In addition, the derivatized siRNA could be delivered without lipofectin complexing and in the presence of serum. The identification of RNAi activity against HIV-1 presents a new approach to study viral infections and a proof of concept of RNAi antiviral activity in mammalian cells.
 ...
PMID:Inhibition of HIV-1 infection by small interfering RNA-mediated RNA interference. 1239 Dec 37

The antiviral efficacies and cytotoxicities of 2',3'- and 4'-substituted 2',3'-didehydro-2',3'-dideoxycytidine analogs were evaluated. All compounds were tested (i) against a wild-type human immunodeficiency virus type 1 (HIV-1) isolate (strain xxBRU) and lamivudine-resistant HIV-1 isolates, (ii) for their abilities to inhibit hepatitis B virus (HBV) production in the inducible HepAD38 cell line, and (iii) for their abilities to inhibit bovine viral diarrhea virus (BVDV) production in acutely infected Madin-Darby bovine kidney cells. Some compounds demonstrated potent antiviral activities against the wild-type HIV-1 strain (range of 90% effective concentrations [EC(90)s], 0.14 to 5.2 micro M), but marked increases in EC(90)s were noted when the compounds were tested against the lamivudine-resistant HIV-1 strain (range of EC(90)s, 53 to >100 micro M). The beta-L-enantiomers of both classes of compounds were more potent than the corresponding beta-D-enantiomers. None of the compounds showed antiviral activity in the assay that determined their abilities to inhibit BVDV, while two compounds inhibited HBV production in HepAD38 cells (EC(90), 0.25 micro M). The compounds were essentially noncytotoxic in human peripheral blood mononuclear cells and HepG2 cells. No effect on mitochondrial DNA levels was observed after a 7-day incubation with the nucleoside analogs at 10 micro M. These studies demonstrate that (i) modification of the sugar ring of cytosine nucleoside analogs with a 4'-thia instead of an oxygen results in compounds with the ability to potently inhibit wild-type HIV-1 but with reduced potency against lamivudine-resistant virus and (ii) the antiviral activity of beta-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine against wild-type HIV-1 (EC(90), 0.08 micro M) and lamivudine-resistant HIV-1 (EC(90) = 0.15 micro M) is markedly reduced by introduction of a 3'-fluorine in the sugar (EC(90)s of compound 2a, 37.5 and 494 micro M, respectively).
 ...
PMID:Antiviral activities and cellular toxicities of modified 2',3'-dideoxy-2',3'-didehydrocytidine analogues. 1243 88

As antiviral nucleosides containing a 2',3'-unsaturated sugar moiety with 2'-fluoro substitution are endowed with increased stabilization of the glycosyl bond, it was of interest to investigate the influence of the fluorine atom at the 3'-position. Various pyrimidine and purine L-3'-fluoro-2',3'-unsaturated nucleosides were synthesized from their precursors, L-3',3'-difluoro-2',3'-dideoxy nucleosides, by elimination of hydrogen fluoride. In the L-3',3'-difluoro-2',3'-dideoxy nucleoside series, cytidine 16 and 5-fluorocytidine 18 analogues showed modest antiviral activity (EC(50) 11.5 and 8.8 microM, respectively) when evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. In the 2',3'-unsaturated series, L-3'-fluoro-2',3'-didehydro-2',3'-dideoxycytidine 24 and 5-fluorocytidine 26 showed highly potent antiviral activity (EC(50) 0.089 and 0.018 microM, respectively) without significant cytotoxicity. The guanosine analogue 48 showed only marginal anti-HIV activity with some cytotoxicity (EC(50) 38.5 microM, and IC(50) 17.4, 58.4, 36.5 microM in PBM, CEM, and Vero cells, respectively). The cytidine 24 and 5-fluorocytidine 26 analogues, however, showed significantly decreased antiviral activity against the clinically important lamivudine-resistant variants (HIV-1(M184V)). Molecular modeling studies demonstrated that the 3'-fluoro atom of the L-3'-fluoro-2',3'-unsaturated nucleoside is within the hydrogen bonding distance with the amide backbone of Asp185, which favors the binding of the nucleoside triphosphate to the wild-type RT. This favorable binding mode, however, cannot be maintained when the triphosphate of 3'-fluoro 2',3'-unsaturated nucleoside binds to the active site of M184V RT because the bulky side chain of Val184 occupies the space needed for the nucleotide. The biological results suggest that, in addition to the sugar conformation, the base moiety may also play a role in their interaction with the M184V RT.
 ...
PMID:l-2',3'-Didehydro-2',3'-dideoxy-3'-fluoronucleosides: synthesis, anti-HIV activity, chemical and enzymatic stability, and mechanism of resistance. 1285 55

HIV-1 transactivating protein Tat is neurotoxic and is believed to play a role in the development of AIDS-associated dementia complex. Neurotoxicity of Tat may be associated with oxidative stress. In this study we examined temporal progression of histopathological changes induced by a single microinjection of Tat 1-72 into the rat striatum. Degenerating neural cells, detected by Fluoro-Jade B staining and increased protein oxidation, determined by protein carbonyl immunostaining, were observed in the striatum as soon as 2 h following the microinjection. Further progression of neuronal degeneration was associated with pronounced infiltration of the area surrounding Tat 1-72 injection site by OX-42 positive macrophages/microglia, which was evident at the 24 h time point. Signs of reactive astrocytosis were found in the striatum of Tat 1-72 injected animals as late as 7 days following the single microinjection. Increased GFAP immunoreactivity and changes in the morphology of astrocytes coincided with a second phase of increased protein carbonyl formation, but not with neuronal degeneration. Control polypeptide, nontoxic Tat delta 31-61, did not cause any cell death, inflammatory reaction or oxidative damage. Results of our study support the hypothesis that oxidative stress may be an early step in the mechanism of Tat neurotoxicity.
 ...
PMID:Temporal relationships between HIV-1 Tat-induced neuronal degeneration, OX-42 immunoreactivity, reactive astrocytosis, and protein oxidation in the rat striatum. 1449 39

Positron emission tomography with fluorine-18-deoxyglucose (FDG-PET) detects active lymphoid tissues during HIV-1 infection in man. We used FDG-PET to study anatomical correlates of HIV-1 infection in man. Whole-body FDG-PET images from 15 patients with HIV-1 showed distinct lymphoid tissue activation in the head and neck during acute disease, a generalised pattern of peripheral lymph-node activation at mid-stages, and involvement of abdominal lymph nodes during late disease. Unexpectedly, HIV-1 progression was evident by distinct anatomical correlates, suggesting that lymphoid tissues are engaged in a predictable sequence. Understanding the anatomy of HIV-1 infection could encourage use of surgical or radiological interventions to supplement chemotherapy.
 ...
PMID:Whole-body positron emission tomography in patients with HIV-1 infection. 1451 30


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>