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)

Antigenic variation among different HIV-1 isolates has been a major problem in the development of an effective vaccine against AIDS. Peptide vaccines incorporating structural elements common to groups of viral isolates, such as the clade subtypes of HIV-1, hold promise; however, the design of such immunogens has been hampered by the lack of specific structural information on the viral proteins to be targeted. As part of a structure-based approach to this problem, we report the design and characterization of a conformationally restricted peptide analog (Aib142) of a highly conserved HIV-1 clade-B sequence from the third variable loop of the membrane glycoprotein gp120. The design strategy incorporates peptide conformational data derived from crystal structure analysis of an MN-isolate peptide (RP142) in complex with the Fab fragment (Fab59.1) of a broadly neutralizing antibody. The synthetic peptide (Aib142) replaces an alanine residue within the V3 loop epitope sequence GPGRAF by the conformationally restricted helicogenic alpha-aminoisobutyryl residue. As expected, the crystal structure of the Fab 59.1-Aib142 complex at 2.8 A resolution shows that the peptide interacts very similarly with the neutralizing antibody. Proton nuclear magnetic resonance (NMR) studies indicate that the free Aib142 peptide is indeed more ordered in solution with a conformational preference that corresponds to the X-ray structure of its Fab-bound form. Aib142 thus represents the first step in the design of conformationally constrained peptide analogs built to mimic biologically relevant structural forms of HIV-1 neutralization sites.
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PMID:Structure-based design of a constrained peptide mimic of the HIV-1 V3 loop neutralization site. 905 68

The viral reverse transcriptase (RT) provides an attractive target in the search for anti-HIV therapies. The nonnucleoside inhibitors (NNIs) are a diverse set of compounds (usually HIV-1 specific) that function by distorting the polymerase active site upon binding in a nearby pocket. Despite being potent and of generally low toxicity, their clinical use has been limited by rapid selection for resistant viral populations. The 2.65-A resolution structure of the complex between HIV-1 RT and the bis(heteroaryl)piperazine (BHAP) NNI, 1-(5-methanesulfonamido-1H-indol-2-yl-carbonyl)-4- [3-(1-methyl-ethylamino) pyridinyl] piperazine (U-90152), reveals the inhibitor conformation and bound water molecules. The bulky U-90152 molecule occupies the same pocket as other NNIs, but the complex is stabilized quite differently, in particular by hydrogen bonding to the main chain of Lys-103 and extensive hydrophobic contacts with Pro-236. These interactions rationalize observed resistance mutations, notably Pro-236-Leu, which occurs characteristically for BHAPs. When bound, part of U-90152 protrudes into the solvent creating a channel between Pro-236 and the polypeptide segments 225-226 and 105-106, giving the first clear evidence of the entry mode for NNIs. The structure allows prediction of binding modes for related inhibitors [(altrylamino)piperidine-BHAPs] and suggests changes to U-90152, such as the addition of a 6 amino group to the pyridine ring, which may make binding more resilient to mutations in the RT. The observation of novel hydrogen bonding to the protein main chain may provide lessons for the improvement of quite different inhibitors.
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PMID:Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor. 910 91

Ascorbic acid (ascorbate or vitamin C) has been shown to suppress the induction of HIV in latently infected T lymphocytic cells following stimulation with a tumor promoter (PMA) and inflammatory cytokine (TNF-alpha). To assess whether this inhibition was mediated via modulation of the cellular transcription factor, NF-kappa B, we carried out gel shift analysis on nuclear extracts prepared under different conditions of cell stimulation in the presence or absence of ascorbate, N-acetylcysteine (NAC), or zidovudine (AZT). Pretreatment of ACH-2 T cells by NAC followed by stimulation with PMA, TNF-alpha, or hydrogen peroxide (H2O2) resulted in strong suppression of NF-kappa B activation. In contrast, neither ascorbate nor AZT affected NF-kappa B activity under all three induction conditions in the ACH-2 cell line. Ascorbate and AZT also had no effect on NF-kappa B activation following TNF-alpha- or PMA-induced stimulation of U1 promonocytic cells. These results suggest that the molecular mechanism of HIV inhibition by ascorbate is not mediated via NF-kappa B inhibition, unlike that seen with other antioxidants.
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PMID:NF-kappa B-independent suppression of HIV expression by ascorbic acid. 911 10

The peptide H-Asn-Ser-Trp-Gly-Cys-Ala-Phe-Arg-Gln-Val-Cys-NHEt corresponding to the 593-603 sequence of gp41 protein of the HIV-2 was used to evaluate different methods for the removal of Acm-protection and subsequent disulfide bond formation. The studied methods involved the treatment by salts of heavy metals (silver and mercury) and subsequent cyclization by oxygen, potassium ferricyanide or hydrogen peroxide. The direct oxidative conversion of Acm-peptide to the corresponding cyclic disulfide by iodine under acidic and neutral conditions was investigated, and the structure of by-products was also studied. The best results were obtained using mercuric acetate followed by oxidation with hydrogen peroxide.
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PMID:Comparative evaluation of different methods for disulfide bond formation in synthesis of the HIV-2 antigenic determinant. 912

We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.
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PMID:Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: synthesis, structure-activity relationship, and X-ray crystal structure analysis. 915 69

Although Schiotz tonometry has been long ago replaced by Goldmann applanation tonometry measurement of intraocular pressure, it remains a viable clinical technique in nursing homes and other "out of office" settings. Because Schiotz tonometers come into contact with the cornea and tear film, they must be properly disinfected to prevent cross-infection with HIV and other infectious pathogens. The Centers for Disease Control and Prevention (CDC) recommends that all eye contact devices be disinfected by a 5- to 10-min soak in one of following disinfectants: 3% hydrogen peroxide, 1:10 sodium hypochlorite (household bleach), or 70% isopropyl alcohol. The effects of these disinfectants on Schiotz tonometers have not been previously investigated. This study investigated the effects of CDC-recommended disinfectants on the structural integrity of Schiotz tonometers. The results of the study indicated that soaking in 1:10 sodium hypochlorite and 3% hydrogen peroxide damaged Schiotz tonometers and rendered them inoperable. Alcohol caused minor damage to the tonometer and was the safest of the CDC disinfectants. This study showed there is limited application of CDC infection control criteria to Schiotz tonometers due to the extensive corrosion and damage caused by hydrogen peroxide and bleach.
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PMID:Structural damage to Schiotz tonometers after disinfection with solutions. 915 7

The (thio)carboxanilide derivatives are potent and selective inhibitors of HIV-1 reverse transcriptase (RT) and have a favourable antiviral activity spectrum. To understand better their mode of action, and to provide a structural basis for further improvement, models of RT complexed with four (thio)carboxanilide inhibitors (UC781, UC10, UC38 and UC84) have been constructed based on the X-ray structure of RT complexed with 9-chloro-TIBO. In the models, the protein conformation is similar to that of the RT-TIBO complex and the complexes are stabilised by hydrogen bonding between the inhibitors and the main chain oxygen of Lys101. Significant hydrophobic interactions include those with Leu100, Val106, Val179, Tyr188, Phe227, Leu234, and His235. The thiocarboxanilides UC781 and UC10 also make important hydrophobic interactions with Trp229. The models are consistent with the inhibitors' relative antiviral potencies and the observed resistance data. They further predict that mutations to Phe227, Trp229, or Leu234 might confer resistance. Since these are not observed, some constraining structural or functional role for these residues in the active enzyme is suggested.
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PMID:Models which explain the inhibition of reverse transcriptase by HIV-1-specific (thio)carboxanilide derivatives. 917 93

The known bisalkylated 2,5-dihydroxybenzoquinones didemethylasterriquinone D and isocochliodinol as well as the new metabolites semicochliodinol A and B have been isolated as inhibitors of HIV-1 protease from the culture broth of the fungus Chrysosporium merdarium P-5656. The structures were elucidated by spectroscopic methods. The NMR spectra of two compounds were completely assigned. The metabolites inhibit HIV-1 protease with an IC50 value as low as 0.17 microM and epidermal growth factor receptor protein tyrosine kinase at 15 to 60 microM and are therefore valuable lead compounds for these targets. Molecular modelling of the HIV-1-protease-inhibitor complexes showed hydrogen bonding between the dihydroxybenzoquinone moiety of didemethylasterriquinone D and isocochliodinol to both active-site aspartic acids (Asp25/Asp25') of the protease and the indole parts of the inhibitors filling the P2 and P2' pockets of the protease.
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PMID:Semicochliodinol A and B: inhibitors of HIV-1 protease and EGF-R protein tyrosine kinase related to asterriquinones produced by the fungus Chrysosporium merdarium. 920 9

We developed and characterized a high-performance liquid chromatography (HPLC) assay for the determination of saquinavir, an HIV protease inhibitor, in human plasma samples. Extraction of plasma samples with diethyl ether resulted in quantitative recovery of both saquinavir and its stereoisomer Ro 31-8533 which was used as an internal standard. The assay was performed isocratically using 5 mM H2SO4 (pH 3.5) and acetonitrile (75.5:24.5, v/v) containing 10 mM tetrabutylammonium hydrogen sulfate (TBA) as a mobile phase, a Nucleosil 3C8 column kept at 45 degrees C and UV detection at 240 nm. Using this method, saquinavir and Ro 31-8533 can be separated from endogenous substances, and in the concentration range of 5-110 ng/ml the relative standard deviations for the determination of saquinavir were below 5%. The detection limit of saquinavir in human plasma was 1 ng/ml. The usefulness of the method was demonstrated by quantification of saquinavir in plasma of human subjects treated with 600 mg of saquinavir per os or 12 mg intravenously.
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PMID:Determination of saquinavir in human plasma by high-performance liquid chromatography. 925 59

Proton MRS has proved useful in the early diagnosis of HIV-related encephalopathy. The modifications of brain metabolism in HIV-related encephalopathy can be classified according to different metabolic patterns (Vion-Dury J et al. CR Acad Sci 1994;317:833-840). The present study describes the relative occurrence of these patterns and evaluates their evolution under zidovudine treatment. We have examined 112 HIV patients--35 neuroasymptomatic patients and 77 patients with ADC (AIDS dementia complex)--with localized proton MRS, using the PRESS 135-msec sequence. We have found the same metabolic modifications in N-acetylaspartate and choline-containing compounds as described in the literature. In addition, 14% of HIV patients with normal MRI displayed abnormal MRS, whatever their neurological status. The MRS-added diagnostic value in neuroasymptomatic patients reaches 30 %. The occurrence of undifferentiated (modification of NAA/Cho ratio only) and Cho (mainly an increase in choline signal) patterns is not significantly different in neuroasymptomatic and ADC patients. The NAA pattern (mainly a significant loss of NAA) is more frequent in ADC patients. Only ADC patients display the double pattern (with a significant increase in choline signal and a significant loss of NAA). Quantitated cerebral atrophy (bifrontal ratio) is related to the occurrence of NAA loss (in NAA and double patterns). An MRS follow-up study of 11 HIV patients showed that the clinical outcome was favorable after a 1000-mg/day zidovudine treatment in patients displaying an NAA pattern whereas this treatment had no effect on the patients displaying the Cho pattern. Consequently, MRS appears to be of great interest in predicting responsiveness to antiretroviral drugs and detecting early any resistance to treatment.
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PMID:Brain proton magnetic resonance spectroscopy in HIV-related encephalopathy: identification of evolving metabolic patterns in relation to dementia and therapy. 926 93


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