Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The crystal structure of a complex between chemically synthesized human immunodeficiency virus type 1 (HIV-1) protease and an octapeptide inhibitor has been refined to an R factor of 0.138 at 2.5-A resolution. The substrate-based inhibitor, H-Val-Ser-Gln-Asn-Leu psi [CH(OH)CH2]Val-Ile-Val-OH (U-85548e) contains a hydroxyethylene isostere replacement at the scissile bond that is believed to mimic the tetrahedral transition state of the proteolytic reaction. This potent inhibitor has Ki less than 1 nM and was developed as an active-site titrant of the HIV-1 protease. The inhibitor binds in an extended conformation and is involved in beta-sheet interactions with the active-site floor and flaps of the enzyme, which form the substrate/inhibitor cavity. The inhibitor diastereomer has the S configuration at the chiral carbon atom of the hydroxyethylene insert, and the hydroxyl group is within H-bonding distance of the two active-site carboxyl groups in the enzyme dimer. The two subunits of the enzyme are related by a pseudodyad, which superposes them at a 178 degrees rotation. The main difference between the subunits is in the beta turns of the flaps, which have different conformations in the two monomers. The inhibitor has a clear preferred orientation in the active site and the alternative conformation, if any, is a minor one (occupancy of less than 30%). A new model of the enzymatic mechanism is proposed in which the proteolytic reaction is viewed as a one-step process during which the nucleophile (water molecule) and electrophile (an acidic proton) attack the scissile bond in a concerted manner.
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PMID:Structure at 2.5-A resolution of chemically synthesized human immunodeficiency virus type 1 protease complexed with a hydroxyethylene-based inhibitor. 199 77

The severity, duration, and reversibility of pentamidine induced bronchial narrowing was studied with and without pretreatment with nebulised terbutaline 10 mg in an open study of 40 patients seropositive for the human immunodeficiency virus (HIV). All subjects received pentamidine 300 mg in 5 ml water via an Acorn System 22 jet nebuliser. The forced expiratory volume in one second (FEV1) fell in all 20 patients given pentamidine alone, the mean maximum fall being 20.6%. In the 20 patients given pentamidine preceded by nebulised terbutaline the mean maximum fall in FEV1 was 4%; three subjects had a fall in FEV1 of more than 10%.
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PMID:Effect of terbutaline on bronchoconstriction induced by nebulised pentamidine. 201 93

A series of 6-substituted 2',3'-dideoxypurine ribofuranosides (ddP) was enzymatically synthesized with live E. coli in an effort to enhance the lipophilicity of this class of anti-human immunodeficiency virus (HIV) compounds and thereby facilitate drug delivery into the central nervous system. All 6-halo-substituted ddPs were substantially more lipophilic, as defined by their octanol-water partition coefficient (P), than their nonhalogenated congeners 2',3'-dideoxyinosine (ddI) or 2',3'-dideoxyguanosine (ddG). For this class of compounds, log P's ranged from +0.5 to -1.2 in the following order: 6-iodo, 2-amino-6-iodo greater than 6-bromo, 2-amino-6-bromo greater than 6-chloro, 2-amino-6-chloro greater than 6-fluoro, 2-amino-6-fluoro much greater than ddG greater than ddI. These compounds were evaluated in vitro for ability to suppress the infectivity, replication, and cytopathic effect of HIV. 2-Amino-6-fluoro-, 2-amino-6-chloro-, and 6-fluoro-ddP exhibited a potent activity against HIV comparable to that of ddI or ddG and completely blocked the infectivity of HIV without affecting the growth of target cells. The comparative order of in vitro anti-HIV activity was 2-amino-6-fluoro, 2-amino-6-chloro, 6-fluoro greater than 2-amino-6-bromo greater than 2-amino-6-iodo, 6-chloro greater than 6-bromo greater than 6-iodo. These compounds also exhibited potent in vitro activity against HIV-2 and 3'-azido-3'-deoxythymidine-resistant HIV-1 variants. All 2-amino-6-halo-ddPs and 6-halo-ddPs were substrates for adenosine deaminase (ADA) and were converted to ddG or ddI, respectively. In the presence of the potent ADA inhibitor 2'-deoxycoformycin, 6-halo-substituted ddPs failed to exert an in vitro antiretroviral effect. These dideoxypurine nucleoside analogues represent a new class of lipophilic prodrugs of ddG and ddI that possess the potential for more effective therapy of HIV-induced neurologic disorders.
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PMID:Escherichia coli mediated biosynthesis and in vitro anti-HIV activity of lipophilic 6-halo-2',3'-dideoxypurine nucleosides. 203 86

The molecular masses, carbohydrate contents, oligomeric status, and overall molecular structure of the env glycoproteins of human immunodeficiency virus type 1--gp120, gp160, and gp41--have been determined by quantitative electron microscopy. Using purified gp160s, a water-soluble form of env purified from a recombinant vaccinia virus expression system, we have measured the masses of several hundred individual molecules by dark-field scanning transmission electron microscopy. When combined with sequence-based information, these mass measurements establish that gp160s is a dimer of subunits with an average monomer mass of 123 kDa, of which approximately 32 kDa is carbohydrate and 91 kDa is protein. Similarly, gp120 was found to be a monomer of 89 kDa and to contain virtually all of env's glycosylation. gp41 is glycosylated only slightly, if at all, and is responsible for the interactions that stabilize the gp160s dimer. A molecular mass map of gp160s derived by image processing depicts an asymmetric dumbbell whose two domains have masses of approximately 173 and approximately 73 kDa, corresponding to a gp120 dimer and a gp41 dimer, respectively. We infer that the average monomer mass of native gp160 is 125 kDa and that in situ, env is either a dimer or a tetramer but is most unlikely to be a trimer.
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PMID:gp160, the envelope glycoprotein of human immunodeficiency virus type 1, is a dimer of 125-kilodalton subunits stabilized through interactions between their gp41 domains. 204 Oct 94

The immune system is a potential target of environmental toxins. Impairment of immune function could have a disastrous effect upon the affected individual. We had the unique opportunity to study the results of a prolonged exposure to TCDD (2,3,7,8-tetrachlorodibenzo-P-dioxin) in rhesus monkeys and their offspring. Subsequently, we performed similar studies on humans exposed to the nematode pesticide, Aldicarb. This report summarizes those previous studies. In the monkeys, no major deficits of the immune system were found and the animals did not have excessive numbers of infections. However, at higher doses of dietary TCDD (25 ppt), only 22% of the offspring survived to 1 year of age. Thus, the failure to demonstrate effects on the young may simply relate to the essential equivalence of the lethal to an immunosuppressive dose. In humans, exposure to the acetylcholinesterase inhibitor, Aldicarb, was received through contaminated well water. The known exposure was for at least 1 year and could have been as long as 5 years. Various tests of the immune system, including lymphocyte subset counts, proliferative responses, total immunoglobulin levels and specific antibody responses did not reveal immunodeficiency. Increases in the numbers of CD8 positive T lymphocytes was observed. There was no evidence of any increase in clinical illness in the exposed compared with the control group.
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PMID:Effects of environmental toxins on lymphocyte function: studies in rhesus and man. 204 62

The conventionally applied centrifugation protocols for the concentration and purification of human immunodeficiency virus type 1 (HIV-1) result in a low recovery of the external glycoprotein, gp120. This is consistent with what has been found with other retroviruses. In the search for a method allowing the copurification of the gp120 with the virion we have applied two-phase extraction based on water-soluble polymers. Several polymer systems were tested for their capacity to enrich HIV-1 from HTLV-IIIB-infected H9 cell culture medium. With a dextran-polyethylene glycol system the gp120 and the gag protein p24, used as marker of the virion, were recovered to about 60 and 70%, respectively, in 1% of the initial volume. The two proteins were both about 30-fold purified and reverse transcriptase activity and infectious titer were retained to a high degree. The calculated molar ratio of gp120 to p24 was twofold higher in the phase-extracted fraction than in material pelleted by ultracentrifugation. It is concluded that extraction in aqueous two-phase systems is a method well suited for the concentration and initial purification of HIV-1. The technique is adaptable to almost any scale and may replace ultracentrifugation. Qualitatively, its main advantage over the latter method is the enhanced recovery of the gp120 in the virion fraction.
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PMID:Extraction of HIV-1 in aqueous two-phase systems to obtain a high yield of gp120. 207 15

We have reported previously (H. R. Kotilainen, J. P. Brinker, J. L. Avato, and N. M. Gantz, Arch. Intern. Med. 149:2749-2753, 1989) that the quality of nonsterile examination gloves available for clinical use may be extremely variable. In view of the concern over human immunodeficiency virus and hepatitis B virus transmission to health care workers, the continuing variability of gloves available for use, and the need for a simple and safe test, we have evaluated 2,500 vinyl (five brands) and 2,000 latex (four brands) gloves by the 300-ml and the newly proposed 1,000-ml water tests and for permeability to herpes simplex virus type 1 and poliovirus type 1, respectively. While all 300-ml watertight gloves were unlikely to leak herpes simplex virus type 1 (1.3% vinyl; 0.5% latex), poliovirus was recovered much more frequently (8.9% vinyl, 6.1% latex). In all gloves that passed the 1,000-ml test, herpes simplex virus type 1 was not recovered. Poliovirus was recovered infrequently (1.4% vinyl, 1.5% latex). Preliminary analyses suggest that the 1,000-ml water test has significantly increased sensitivity over the 300-ml water test in the detection of small holes in both vinyl and latex gloves that may allow the passage of viral particles. Gloves that pass a 1,000-ml water challenge are unlikely to allow the passage of a small virus such as poliovirus. Given that human immunodeficiency virus, hepatitis B virus and herpes simplex virus type 1 are larger particles than poliovirus, gloves that pass the 1,000-ml water test theoretically could provide better protection.
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PMID:Latex and vinyl nonsterile examination gloves: status report on laboratory evaluation of defects by physical and biological methods. 216 69

Contact lens (CL) fitting carries the risk of transmitting infectious agents, including adenovirus and Pseudomonas. Therefore, a number of precautions must be observed to ensure safety in the office. Paramount among these is hand washing, both immediately after contact with a patient's eyes and again between patients. Equally important is that all trial lenses and CLs removed from patients be disinfected before reuse. Low-water-content soft CLs can be heat disinfected; high-water-content CLs require chemical treatment. A combination of surfactant cleaning with a chlorhexidine-containing agent and hydrogen peroxide disinfection is preferred for rigid lenses to guarantee destruction of human immunodeficiency virus (HIV). The proper use of lens care solutions is also necessary to minimize the risk of their becoming contaminated with pathogenic organisms. Only commercially prepared solutions should be used, preferably in small-volume bottles that are frequently replaced. Preservative-free solutions should be discarded after 1 day's use, whereas preserved solutions may be used for up to 2 weeks. Sterile saline rather than tap water is recommended for rinsing rigid lenses. Finally, part of the clinician's responsibility in running a safe office is to educate patients about these hygienic practices.
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PMID:Is your office safe? Yes. 218 80

The water-soluble ammonium salt of 3'-azido-5'-(O-ethoxycarbonylphosphinyl)-3'-deoxythymidine (ECP-AZT), the prototype of a novel class of compounds incorporating two active antiretroviral agents, in this case 3'-azido-3'-deoxythymidine (AZT) and phosphonoformic acid (PFA), within the same structure, was synthesized and tested as an inhibitor of the replication of human immunodeficiency virus type 1 (HIV-1) in Jurkat cells, a CD4+ human T-lymphocyte cell line. The corresponding 5'-(O-methoxycarbonylphosphinyl) derivative (MCP-AZT) was also prepared. The rationale for the synthesis of ECP-AZT and MCP-AZT was that they may be cleaved intracellularly to AZT and PFA via hydrolysis of the phosphate ester bond or to AZT 5'-monophosphate by oxidative cleavage of the carbon-phosphorus bond. ECP-AZT was found to block viral replication at a 50% inhibitory concentration (IC50) of ca. 10(-6) M as measured by reverse transcriptase (RT) activity in supernatants from cultures of infected cells. Little or no inhibition of cell growth was observed at this concentration, and there was less than 20% inhibition of cell growth at 10(-4) M. AZT itself was a more potent inhibitor of HIV-1 replication than ECP-AZT, but was also more cytotoxic. The antiviral selectivity of ECP-AZT, defined as the ratio IC50 (virus inhibition)/IC50(cell growth inhibition), was in the range considered to be therapeutic for anti-AIDS nucleosides.
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PMID:Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate esters of 3'-azido-3'-deoxythymidine. 222 76

Increased extracellular concentrations of uridine (Urd) have been reported to reduce, in vitro, azidothymidine (AZT)-induced inhibition of human granulocyte-macrophage progenitor cells without impairment of its antihuman immunodeficiency virus (HIV) activity. Because of the clinical toxicities associated with chronic Urd administration, the ability of benzylacyclouridine (BAU) to effect, in vivo, AZT-induced anemia and leukopenia was assessed. This agent inhibits Urd catabolism and, in vivo, increases the plasma concentration of Urd in a dose-dependent manner, without Urd-related toxicity. In mice rendered anemic and leukopenic by the administration of AZT for 28 days in drinking water (1.5 mg/mL), the continued administration of AZT plus daily BAU (300 mg/kg, orally) partially reversed AZT-induced anemia and leukopenia (P less than .05), increased peripheral reticulocytes (to 4.9%, P less than .01), increased cellularity in the marrow, and improved megaloblastosis. When coadministered with AZT from the onset of drug administration, BAU reduced AZT-induced marrow toxicity. In vitro, at a concentration of 100 mumol/L, BAU possesses minimal anti-HIV activity and has no effect on the ability of AZT to reverse the HIV-induced cytopathic effect in MT4 cells. The clinical and biochemical implications of these findings are discussed.
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PMID:Benzylacyclouridine reverses azidothymidine-induced marrow suppression without impairment of anti-human immunodeficiency virus activity. 225 94


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