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 crystal structure of HIV-2 protease in complex with a reduced amide inhibitor [BI-LA-398; Phe-Val-Phe-psi (CH2NH)-Leu-Glu-Ile-amide] has been determined at 2.2-A resolution and refined to a crystallographic R factor of 17.6%. The rms deviation from ideality in bond lengths is 0.018 A and in bond angles is 2.8 degrees. The largest structural differences between HIV-1 and HIV-2 proteases are located at residues 15-20, 34-40, and 65-73, away from the flap region and the substrate binding sites. The rms distance between equivalent C alpha atoms of HIV-1 and HIV-2 protease structures excluding these residues is 0.5 A. The shapes of the S1 and S2 pockets in the presence of this inhibitor are essentially unperturbed by the amino acid differences between HIV-1 and HIV-2 proteases. The interaction of the inhibitor with HIV-2 protease is similar to that observed in HIV-1 protease structures. The unprotected N terminus of the inhibitor interacts with the side chains of Asp-29 and Asp-30. The glutamate side chain of the inhibitor forms hydrogen bonds with the main-chain amido groups of residues 129 and 130.
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PMID:Crystal structure of human immunodeficiency virus (HIV) type 2 protease in complex with a reduced amide inhibitor and comparison with HIV-1 protease structures. 837 11

A series of glycopeptidemimetics based on the hydroxyethylene Phe-Phe isostere have been synthesized and evaluated for their ability to inhibit the enzyme HIV-1 protease. Incorporation of carbohydrate moieties at the P'2-position and elimination of P'3 amino acid in our lead compound 1, provided inhibitors with only nanomolar potencies (400-800 nM). However, incorporation of a carbohydrate moiety at the P'3-position with branched chain amino acid at the P'2-position, resulted in inhibitors with subnanomolar potencies. Within this series, compound 21 was the most potent inhibitor (IC50 value 0.17 nM). This compound has also shown to block the spread of HIV-1 in T-lymphoid cells at an inhibitor concentration of 200 nM.
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PMID:HIV-1 protease inhibitors: synthesis and biological evaluation of glycopeptidemimetics. 839 95

We showed previously that a commercially available synthetic tetradecapeptide, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser, produces authentic angiotensin I (Ang I) upon incubation with the HIV-1 protease (S. K. Sharma et al., Anal. Biochem. 198:363, 1991). Therefore, we developed an Ang-I based activity assay for HIV protease inhibitors based on the technology developed earlier (M. J. Ruwart et al., Pharm. Res. 7:407, 1990; S. K. Sharma et al., Anal. Biochem. 186:24, 1990) for tracking renin inhibitors in rat sera. Ditekiren was either extracted from sera with ethyl acetate or assayed after the interfering substances in sera were precipitated with acetonitrile. Purified recombinant HIV-1 protease was added to extracted rat serum and the enzymatic reaction was initiated in the presence of the tetradecapeptide substrate. The inhibition of Ang I production was measured by a commercially available RIA kit. The cleanup methodology also enabled a commercially available Proteinase Scintillation Proximity Assay (SPA, Amersham) to quantify ditekiren in rat serum through the addition of recombinant HIV-1 protease and cleavage of substrate from SPA beads. Results were confirmed by HPLC or by the renin assay for ditekiren, which inhibits both aspartyl proteases. These technologies should prove useful for assessing serum levels of HIV protease inhibitors in rat.
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PMID:Development of activity assays for high-volume evaluation of human immunodeficiency virus (HIV) protease inhibitors in rat serum: results with ditekiren. 848 39

The atomic structure of a truncated glycoprotein gp120 from human immunodeficiency virus 1 (HIV-1) that contains the principal neutralizing antigenic sites and the CD4 binding domain has been derived by molecular dynamics and calculation of potential energy using the DREIDING force field. The resultant N-glycosylated molecular model is consistent with known properties of gp120 and docks with CD4 with a substantial reduction in the sum of the internal potential energies of the individual proteins (delta E = -200 kcal/mol). The primary mechanism of recognition and binding is the insertion of the solvent-accessible Phe-43 of CD4 into a gp120 solvent-accessible acceptor pit formed by Trp-427, Tyr-435, and the high-mannose oligosaccharide N-linked to Asn-230. delta E for the nonglycosylated complex is reduced significantly (-75 kcal/mol). Binding is by pi-pi* interactions of the aromatic groups forming a hydrophobic, thermodynamically stable environment for these functional noncovalent bonding participants. This model for gp120 provides a theoretical basis for the evaluation of HIV molecular pathogenesis involving the env proteins, the analysis of conformation on functional immune response of the host, and the design of nonproteinaceous inhibitors specific for the CD4 binding site on gp120.
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PMID:Proposed atomic structure of a truncated human immunodeficiency virus glycoprotein gp120 derived by molecular modeling: target CD4 recognition and docking mechanism. 848 33

Hydrosoluble macromolecular fluorogenic substrates specific for the human immunodeficiency virus 1 (HIV-1) proteinase have been prepared. The fluoresceinyl peptide Ftc-epsilon-Ahx-Ser-Phe-Asn-Phe-Pro-Gln-Ile-Thr-(Gly)n, corresponding to the first cleavage site of HIV-1 gag-pol native precursor was linked to a water-soluble neutral (Lys)n derivative. The epsilon-aminohexanoyl residue (epsilon-Ahx) and the glycyl sequence were added in order to improve the stability of the substrate and the accessibility of the cleavage site to the HIV-1 proteinase respectively. This macro-molecular peptidic-substrate conjugate is significantly more water-soluble than the free peptide itself on a substrate molar concentration basis. The assay is based on the quantitative precipitation of the polymeric material by adding propan-2-ol whereas the fluorescent peptide moiety released upon proteolysis remains soluble in the supernatant. The proteinase activity is assessed by measuring the fluorescence of the supernatant. This assay allows the detection of a few fmol of HIV-1 proteinase, even in the presence of cell culture media, plasma or cell lysate and it gives accurate results within a large proteinase concentration range. The hydrosoluble macromolecular substrate is also suitable for determining the HIV-1 proteinase activity using 96-well microplates, allowing us to test accurately and rapidly numerous enzyme samples and/or the potency of new proteinase inhibitors.
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PMID:Sensitive, hydrosoluble, macromolecular fluorogenic substrates for human immunodeficiency virus 1 proteinase. 848 13

During May 1988-October 1990 in Zaire, Neisseria gonorrhoeae isolates were obtained from 650 initially HIV-negative prostitutes in Kinshasa who were followed monthly for 30 months. After conservation of the gonococci, the N. gonorrhoeae isolates were then transported to the Institute of Tropical Medicine in Antwerp, Belgium, to test for antimicrobial resistance, especially tetracycline resistant isolates of N. gonorrhoeae. Among the 1085 isolates, 67% were resistant to penicillin (i.e., penicillinase producing N. gonorrhoeae [PPNG]). 30% exhibited plasmid-mediated resistance to tetracycline (TRNG). 37% were resistant to thiamphenicol. Thiamphenicol resistance was more common in non-TRNG isolates than TRNG isolates (49% vs. 8%; p 0.0001). The frequency of TRNG among PPNG isolates was higher than it was among non-PPNG isolates (37% vs. 16%; p 0.001). PPNG prevalence ranged from 60% to 73%. TRNG prevalence increased steadily from 11% to 45% during the 30-month period. Both TRNG and PPNG isolates were significantly associated with the auxotype/serovar class Pro-/IA-6 (p 0.0001 and p = 0.0002, respectively). They were also associated with growth inhibition by 0.25 mM phenylalanine (p 0.0001 and p = 0.001, respectively). The number of different TRNG auxotype/serovar classes ranged from 6 to 13. It has been suggested that tetracycline use to control gonorrhea in the US and in the Netherlands increased the frequency and spread of TRNG. Only spectinomycin and ciprofloxacin were used to treat gonorrhea in this study. Yet, tetracycline was prescribed for genital Chlamydia trachomatis infection, which many of the prostitutes had. Also, males self-medicate for urethritis with tetracycline. Populations with a high incidence of gonococcal infections may experience an epidemic spread of TRNG.
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PMID:Epidemic spread of plasmid-mediated tetracycline resistant Neisseria gonorrhoeae in Zaire. 854 15

The HIV-1 protease (PR) is essential for the production of mature virions. As such, it has become a target for the development of anti-HIV chemotherapeutics. Multiple passages of virus in cell culture in the presence of PR inhibitors have resulted in the selection of variants with decreased sensitivity to inhibitors of the PR. The most common alteration observed is a single amino acid change at position 82. This particular position has been well characterized by several laboratories as being important for the susceptibility of the virus to inhibitors of PR function. Mutations which result in the substitution of the wild-type valine with alanine, phenylalanine, threonine or isoleucine at position 82 of the PR have been associated with decreased sensitivity to several PR inhibitors. We describe here a clinical strain of HIV-1 that contains an isoleucine at position 82 of the PR instead of the usual valine. This strain is unique in that it was isolated from a patient that was anti-retroviral naive, and in the past, variants at position 82 of the PR have only been found after treatment of patients or cell culture with PR inhibitors. Moreover, this virus remains sensitive to PR inhibitors of the cyclic urea and C-2 symmetrical diol classes.
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PMID:Identification of a clinical isolate of HIV-1 with an isoleucine at position 82 of the protease which retains susceptibility to protease inhibitors. 858 57

Drug resistance in tuberculosis (TB) has become a major public health threat, particularly when the disease cannot be 100% controlled by BCG vaccination. In Thailand, resistance to rifampicin, a major component of multidrug regimens of treatment, is the common cause of tuberculosis recurrence. The mechanism of rifampicin resistance involves alterations of the RNA polymerase subunit beta (rpo B) gene. Mutations in rpo B gene were often found to cluster within a region of 23 amino acids starting from amino acid residue 511 to residue 533. Direct PCR sequencing was utilized to compare base changes in rpo B gene in three rifampicin resistant phenotypes of M. tuberculosis isolated from Thai patients. The sequences showed one base substitution at codon 531 resulting in an amino acid change from serine (TCG) to leucine (TTG) in a multidrug resistant isolate compared to that of a sensitive isolate, whereas a point mutation at codon 516 causing a change from aspartic acid (GAC) to tyrosine (TAC) was detected in a multidrug resistant isolate from a HIV positive patient. In an isolate resistant only to rifampicin a double mutation at codon 531 changing serine (TCG) to phenylalanine (TTT) was found. No mutations were observed in the same region in streptomycin, ethambutol or isoniazid resistant isolates. This finding reports two new types of mutation (GAC to TAC at codon 516 and TCG to TTT at codon 531) and confirms a direct correlation between rpo B gene alteration and rifampicin resistant phenotype in M. tuberculosis.
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PMID:Analysis of RNA polymerase gene mutation in three isolates of rifampicin resistant Mycobacterium tuberculosis. 862 37

Passage of human immunodeficiency virus type-1 (HIV-1) in T-lymphocyte cell lines in the presence of increasing concentrations of the hydroxylethylamino sulfonamide inhibitor VX-478 or VB-11328 results in sequential accumulation of mutations in HIV-1 protease. We have characterized recombinant HIV-1 proteases that contain these mutations either individually (L10F, M46I, I47V, I50V) or in combination (the double mutant L10F/I50V and the triple mutant M46I/I47V/I50V). The catalytic properties and affinities for sulfonamide inhibitors and other classes of inhibitors were determined. For the I50V mutant, the efficiency (kcat/Km) of processing peptides designed to mimic cleavage junctions in the HIV-1 gag-pol polypeptide was decreased up to 25-fold. The triple mutant had a 2-fold higher processing efficiency than the I50V single mutant for peptide substrates with Phe/Pro and Tyr/Pro cleavage sites, suggesting that the M46I and I47V mutations are compensatory. The effects of mutation on processing efficiency were used in conjunction with the inhibition constant (Ki) to evaluate the advantage of the mutation for viral replication in the presence of drug. These analyses support the virological observation that the addition of M46I and I47V mutations on the I50V mutant background enables increased survival of the HIV-1 virus as it replicates in the presence of VX-478. Crystal structures and molecular models of the active site of the HIV-1 protease mutants suggest that changes in the active site can selectively affect the binding energy of inhibitors with little corresponding change in substrate binding.
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PMID:Kinetic characterization of human immunodeficiency virus type-1 protease-resistant variants. 866 9

P18(IIIB) is a highly immunogenic peptide from the V3 loop of the HIV-1 gp160 envelope protein that is presented promiscuously by multiple class I MHC molecules. Understanding the molecular basis for promiscuous presentation may have many practical applications. As the highly prevalent HLA-A2.1 class I molecule is known to present P18(IIIB) for recognition by cytotoxic T lymphocytes (CTL) found in peripheral blood mononuclear cells of HIV+ donors, a P18(IIIB)-specific CTL line was generated from and HLA-A2(+), HIV- donor in order to define the molecular basis for, and ultimately improve upon the binding of, this peptide to HLA-A2.1. The minimal epitope recognized by the line was a decamer, I10, with the sequence RGPGRAFVTI. Interestingly, this decamer is identical to the minimal epitope from P18(IIIB) seen by murine CTL restricted by H-2Dd. A panel of Ala-substituted peptides was employed in MHC-binding and T cell response studies to identify MHC- and TCR-binding residues. Notably, many of the agretopic and epitopic residues identified were identical to those involved in the corresponding interactions of I10 with the H-2Dd MHC molecule and murine I10-specific CTL. The I10 peptide does not contain the described HLA-A2.1 binding motif. Instead a Pro at P3, a Phe at P7 and an Ile at P10 are utilized for MHC binding. Agretopic residue similarities with the hepatitis B nucleocapsid decamer suggest that these residues may comprise an alternative motif of anchors utilized by decamers for binding to HLA-A2.1.
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PMID:Molecular analysis of presentation by HLA-A2.1 of a promiscuously binding V3 loop peptide from the HIV-envelope protein to human cytotoxic T lymphocytes. 867 51


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