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)

Analogues of peptides ranging in size from three to six amino acids and containing the hydroxyethylene dipeptide isosteres Phe psi Gly, Phe psi Ala, Phe psi NorVal, Phe psi Leu, and Phe psi Phe, where psi denotes replacement of CONH by (S)-CH(OH)CH2, were synthesized and studied as HIV-1 protease inhibitors. Inhibition constants (Ki) with purified HIV-1 protease depend strongly on the isostere in the order Phe psi Gly greater than Phe psi Ala greater than Phe psi NorVal greater than Phe psi Leu greater than Phe psi Phe and decrease with increasing length of the peptide analogue, converging to a value of 0.4 nM. Ki values are progressively less dependent on inhibitor length as the size of the P1' side chain within the isostere increases. The structures of HIV-1 protease complexed with the inhibitors Ala-Ala-X-Val-Val-OMe, where X is Phe psi Gly, Phe psi Ala, Phe psi NorVal, and Phe psi Phe, have been determined by X-ray crystallography (resolution 2.3-3.2 A). The crystals exhibit symmetry consistent with space group P6(1) with strong noncrystallographic 2-fold symmetry, and the inhibitors all exhibit 2-fold disorder. The inhibitors bind in similar conformations, forming conserved hydrogen bonds with the enzyme. The Phe psi Gly inhibitor adopts an altered conformation that places its P3' valine side chain partially in the hydrophobic S1' pocket, thus suggesting an explanation for the greater dependence of the Ki value on inhibitor length in the Phe psi Gly series. From the kinetic and crystallographic data, a minimal inhibitor model for tight-binding inhibition is derived in which the enzyme subsites S2-S2' are optimally occupied. The Ki values for several compounds are compared with their potencies as inhibitors of proteolytic processing in T-cell cultures chronically infected with HIV-1 (MIC values) and as inhibitors of acute infectivity (IC50 values). There is a rank-order correspondence, but a 20-1000-fold difference, between the values of Ki and those of MIC or IC50. IC50 values can approach those of Ki but are highly dependent on the conditions of the acute infectivity assay and are influenced by physiochemical properties of the inhibitors such as solubility.
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PMID:Hydroxyethylene isostere inhibitors of human immunodeficiency virus-1 protease: structure-activity analysis using enzyme kinetics, X-ray crystallography, and infected T-cell assays. 163 5

Tertiary models of ribonuclease H (RNase H) domains in reverse transcriptases (RTs) from Moloney murine leukemia virus (MuLV) and human immunodeficiency virus (HIV-1) were built based upon the X-ray structure of RNase H from Escherichia coli (E. coli RNase H). In two models of RT-RNase H domains, not only active site residues but also residues, which construct a hydrophobic core and hydrogen bonds, are located in the same positions as those of E. coli RNase H. The whole backbone structure and the electrostatic molecular surface of MuLV RT-RNase H model are similar to those of E. coli RNase H. On the contrary, HIV-1 RT-RNase H model lacks the third helix and the following loop, resulting no positive charge clusters around the hybrid recognition site. Referring the complex models of RTs with their substrate hybrid, the interaction between DNA-polymerase and RNase H domains in RTs was discussed.
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PMID:Structural models of ribonuclease H domains in reverse transcriptases from retroviruses. 170 92

Short peptides that contain the basic region of the HIV-1 Tat protein bind specifically to a bulged region in TAR RNA. A peptide that contained nine arginines (R9) also bound specifically to TAR, and a mutant Tat protein that contained R9 was fully active for transactivation. In contrast, a peptide that contained nine lysines (K9) bound TAR poorly and the corresponding protein gave only marginal activity. By starting with the K9 mutant and replacing lysine residues with arginines, a single arginine was identified that is required for specific binding and transactivation. Ethylation interference experiments suggest that this arginine contacts two adjacent phosphates at the RNA bulge. Model building suggests that the arginine eta nitrogens and the epsilon nitrogen can form specific networks of hydrogen bonds with adjacent pairs of phosphates and that these arrangements are likely to occur near RNA loops and bulges and not within double-stranded A-form RNA. Thus, arginine side chains may be commonly used to recognize specific RNA structures.
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PMID:Arginine-mediated RNA recognition: the arginine fork. 170 22

The recent finding that 3'-amino-3'-deoxythymidine 5'-triphosphate is a noncompetitive inhibitor of the HIV-1 reverse transcriptase (Kedar, P.S.; et al. Biochemistry 1990, 29, 3603-3611), prompted an investigation of the conformation of 3'-amino-3'-deoxythymidine. An X-ray diffraction study has revealed that the glycosidic torsion angle of the nucleoside is in the less common syn region and this solid-state geometry is stabilized by a three-dimensional network of self-associated hydrogen-bonded molecules. On the other hand, the aqueous solution conformation, as determined by 1H NMR, places the glycosidic torsion angle in the more usual anti region with the sugar in an equilibrium between C3'-endo and C2'-endo puckering. The energy barrier between the solid-state and solution conformation is relatively low as was demonstrated by the MM2 calculations.
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PMID:Solid-state and solution conformation of 3'-amino-3'-deoxythymidine, precursor to a noncompetitive inhibitor of HIV-1 reverse transcriptase. 171 58

A rapid and simple screening test for antibodies to HIV-1 was designed on the principle of dot-EIA. Recombinant HIV-1 env and gag polypeptides are fixed on nitrocellulose sheets. Peroxidase conjugated protein A is used for detection of bound antibodies. After addition of hydrogen peroxide and 2-bromo-1-naphtol antigen-antibody complexes are visualized as discrete blue coloured spots. The test is completed within 15 min. Out of 111 sera positive by commercial EIA and Western blot analysis 110 were recognized by dot-EIA (sensitivity: 99.1%). False positive results compared with commercial EIA were found in 2 of 423 healthy blood donors (specificity: 99.5%).
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PMID:Rapid, easy and economical dot EIA for detection of antibodies to HIV-1 using recombinant env- and gag-proteins. 180 49

A solution hybridization assay using acridinium ester labelled probes is described for detection of amplified HIV-1 DNA segments. Amplification was achieved by 30 cycles of the polymerase chain reaction using SK38/SK39 primers specific for a constant region of the HIV-1 gag region together with HLA DQ alpha primers as internal control. Discrimination between hybridized and non-hybridized probes by differential hydrolysis resulted in a three log reduction of the chemiluminescence signal of the non-hybridized probe within 6 min without significant changes in the hybridized probes due to protection of the acridinium ester to hydrolysis by intercalation formation. Chemiluminescence was measured by a two-step-injection method with hydrogen-peroxide and NaOH. About 50 attomols of HIV-1 gag DNA could be detected. Chemiluminescence results, given in relative light units (RLU) of 159 HIV-1-infected patients (range 4013-458319) showed clear discrimination from 64 noninfected control samples (range 838-1477) (cut off 2000 RLU). Comparison with parallel detection of amplified products with autoradiography (32P) and ethidium bromide-stained agarose gels or a p24 antigen ELISA demonstrated better sensitivity and reproducibility of the chemiluminescence assay. The time required for the assay, including measurements, is less than 30 min, which allows reporting 'PCR results' on the same day.
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PMID:A rapid chemiluminescence detection method for PCR-amplified HIV-1 DNA. 187 18

The different isolates available for HIV-1 and HIV-2 were compared for the region of the protease (PR) sequence, and the variations in amino acids were analyzed with respect to the crystal structure of HIV-1 PR with inhibitor. Based on the extensive homology (39 identical out of 99 residues), models were built of the HIV-2 PR complexed with two different aspartic protease inhibitors, acetylpepstatin and a renin inhibitor, H-261. Comparison of the HIV-1 PR crystal structure and the HIV-2 PR model structure and the analysis of the changes found in different isolates showed that correlated substitutions occur in the hydrophobic interior of the molecule and at surface residues involved in ionic or hydrogen bond interactions. The substrate binding residues of HIV-1 and HIV-2 PRs show conservative substitutions of four residues. The difference in affinity of HIV-1 and HIV-2 PRs for the two inhibitors appears to be due in part to the change of Val 32 in HIV-1 PR to Ile in HIV-2 PR.
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PMID:Comparative analysis of the sequences and structures of HIV-1 and HIV-2 proteases. 194 42

Nuclear magnetic resonance (NMR) methods have been used to address issues regarding the relevance and feasibility of zinc binding to "zinc finger-like" sequences of the type C-X2-C-X4-H-X4-C [referred to as CCHC or retroviral-type (RT) zinc finger sequences]. One-dimensional (1D) NMR experiments with an 18-residue synthetic peptide containing the amino acid sequence of an HIV-1 RT-zinc finger domain (HIV1-F1) indicate that the sequences are capable of binding zinc tightly and stoichiometrically. 1H-113Cd spin echo difference NMR data confirm that the Cys and His amino acids are coordinated to metal in the 113Cd adduct. The 3D structure of the zinc adduct [Zn(HIV1-F1)] was determined to high atomic resolution by a new NMR-based approach that utilizes 2D-NOESY back-calculations as a measure of the consistency between the structures and the experimental data. Several interesting structural features were observed, including (1) the presence of extensive internal hydrogen bonding, and (2) the similarity of the folding of the first six residues to the folding observed by X-ray crystallography for related residues in the iron domain of rubredoxin. Structural constraints associated with conservatively substituted glycines provide further rationale for the physiological relevance of the zinc adduct. Similar NMR and structural results have been obtained for the second HIV-1 RT-zinc finger peptide, Zn(HIV1-F2). NMR studies of the zinc adduct with the NCP isolated directly from HIV-1 particles provide solid evidence that zinc finger domains are formed that are conformationally similar (if not identical) to the peptide structures.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Zinc finger motif for single-stranded nucleic acids? Investigations by nuclear magnetic resonance. 200 83

The nutritional needs of children with human immunodeficiency virus infection are poorly understood. Twenty-eight children with vertically transmitted human immunodeficiency virus infection were evaluated for carbohydrate malabsorption using lactose hydrogen breath tests and d-xylose absorption studies. Lactose malabsorption was a common finding in human immunodeficiency virus-infected children and occurred in 8 of 20 patients who had no identifiable enteric pathogen. Lactose malabsorption occurred at an earlier age in human immunodeficiency virus-infected children than in an age-matched group of 45 symptomatic control children (P = 0.02). However, lactose malabsorption was not associated with higher rates of diarrhea or growth failure. Abnormalities in d-xylose absorption were not significantly associated with either diarrhea or growth failure. However, 39% of d-xylose studies (9 of 23) showed abnormal results and were significantly associated with enteric infections (P = 0.004). Abnormalities in small-bowel morphology were found in 4 of 9 children with growth failure, 3 of whom had an enteric infection and low d-xylose absorption. Lactose hydrogen breath testing and d-xylose testing showed carbohydrate malabsorption in 61% of children (17 of 28). This study demonstrates that human immunodeficiency virus-infected children are at risk for malabsorptive disorders, which are not always related to clinical symptoms. We speculate that human immunodeficiency virus may be directly involved in the development of lactose malabsorption. Carbohydrate malabsorption in human immunodeficiency virus-infected children may not be the only factor responsible for growth failure.
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PMID:Malnutrition and carbohydrate malabsorption in children with vertically transmitted human immunodeficiency virus 1 infection. 201 74

In order to obtain agents with therapeutic indices superior to those of AZT, FLT, or D4T, several analogues of anti-HIV-1 nucleosides were synthesized. These include 2',3'-dideoxy-2',3' -difluoro-5-methyluridine (13), its arabino analogue 19, arabino-5-methylcytosine analogue 21, 3'-deoxy-2',3'-didehydro-2' -fluorothymidine (25), 3'-azido-2',3'-dideoxy-2'-fluoro-5-methyluridine (29), 2'-azido-3'-fluoro-2',3'-dideoxy-5-methyluridine (31), and 2'3'-dideoxy-2' -fluoro-5-methyluridine (37). These new nucleosides were screened for their activity against HIV and feline TLV in vitro. None of the compounds showed significant activity. It is interesting to note that such a small modification in the sugar moiety of active anti-HIV nucleosides (i.e., displacement of hydrogen by fluorine) almost completely inactivate the agents.
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PMID:Fluorinated sugar analogues of potential anti-HIV-1 nucleosides. 203 90


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