Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 aspartyl protease of the human immunodeficiency virus (HIV) is an important target for chemotherapeutic intervention because of its key role in cleaving the HIV gag-pol polyprotein during viral assembly and budding. Short peptides and peptidomimetics, which bind to the active site of the HIV aspartyl protease and inhibit processing of the polyprotein, have been synthesized. These compounds are active against HIV in vitro, but many face substantial development problems because of their rapid elimination from the body in bile and urine. Refinement of these agents appears to be necessary if they are to become useful clinically. Recently, we developed a novel chemical strategy for increasing plasma levels of HIV protease inhibitory peptides, which involves the attachment of a biodegradable phospholipid group to the C-terminus of a pentapeptide, iBOC-[L-Phe]-[D-beta-Nal]-Pip-[alpha-(OH)-Leu]-Val (7194). We coupled phosphatidylethanolamine to the C-terminal valine of 7194 to make a phospholipid prodrug (7196). In vitro assays in HT4-6C cells infected with HIV-1 showed that the antiviral activity of the C-terminal phospholipid prodrug, 7196, was equal to that of the free peptide, 7194. Similar results were obtained in vitro when a related pentapeptide (7140) was derivatized at the N-terminal with dipalmitoylphosphatidylethanolamine-succinic acid (7172). Tritium-labeled 7194 and 7196 were prepared and injected intravenously into rats at 3 mumol/kg; then the plasma was assayed for native compound and metabolites by HPLC radioactivity flow detection. The peak plasma level of the tritium-labeled lipid prodrug (7196) was 36 microM versus 1.6 microM for the free protease inhibitor pentapeptide (7194). The area under the curve of the phospholipid prodrug (7196) was 48-fold greater and its mean residence time was increased 43-fold versus the free peptide (7194). Phospholipid prodrugs appear to offer an alternative approach to optimizing in vivo performance of HIV protease inhibitors and other small peptides.
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PMID:Phospholipid prodrug inhibitors of the HIV protease. Antiviral activity and pharmacokinetics in rats. 794 39

The discovery of therapeutic agents has, in the past, started primarily with random screening efforts. These screens, although effective, are time-consuming and expensive. Attempts are now being made to design more efficient methods of screening that take into account available information about the three-dimensional structure of a target receptor or enzyme. In the case of acquired immunodeficiency syndrome, the structure of a proteolytic enzyme, the human immunodeficiency virus (HIV) protease, an aspartyl protease that plays a crucial role in the viral life cycle, has been determined and extensively characterized. Using the protease structure and the computer program DOCK, the active site of the protease was mapped and its shape used to screen a subset of the Cambridge Structural Database. Among the molecules whose shape was complementary to the active site was the antipsychotic agent haloperidol. This molecule and several chemically modified derivatives were shown to bind competitively with micromolar affinity to the HIV protease but not to cellular aspartyl proteases. X-ray structures of the HIV protease complexed with haloperidol derivatives show the molecules binding in the predicted position at the active site. In an attempt to overcome the problems associated with low-affinity competitive inhibitors, reactive groups that enable the molecule to serve as a specific irreversible inhibitor of the HIV protease were introduced onto the haloperidol scaffold. These inhibitors demonstrated an ability to block viral polyprotein processing in a tissue culture model of HIV-1 infection, although their cytotoxicity is pronounced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Structure-assisted design of nonpeptide human immunodeficiency virus-1 protease inhibitors. 795 56

Pepstatin A, a pentapeptide with the molecular weight of 686, is a naturally occurring inhibitor of aspartyl proteases secreted by Streptomyces species. Above a critical concentration of 0.1 mM at low ionic strength and neutral pH, it can polymerize into filaments which may extend over several micrometers. After negative staining, these filaments show a helical substructure with characteristic diameters ranging from 6 to 12 nm. Selected images at higher magnification suggest the filaments are composed of two intertwined 6 nm strands. This is in agreement with the optical diffraction analysis which additionally established a periodic pitch of 25 nm for the helical intertwining. Rotary shadowing of the pepstatin A filaments clearly demonstrated the right-handedness of the helical twist. In physiological salt solution or at higher concentrations of pepstatin A, a variety of higher order structures were observed, including ribbons, sheets and cylinders with both regular and twisted or irregular geometries. Pepstatin A can interact with intermediate filament subunit proteins. These proteins possess a long, alpha-helical rod domain that forms coiled-coil dimers, which through both hydrophobic and ionic interactions form tetramers which, in turn, in the presence of physiological salt concentrations, polymerize into the 10 nm intermediate filaments. In the absence of salt, pepstatin A and intermediate filament proteins polymerize into long filaments with a rough surface and a diameter of 15-17 nm. This polymerization appears to be primarily driven by nonionic interactions between pepstatin A and polymerization-competent forms of intermediate filament proteins, resulting in a composite filament. Polymerization-incompetent proteolytic fragments of vimentin, lacking portions of the head and/or tail domain, failed to copolymerize with pepstatin A into long filaments under these conditions. These peptides, as well as bovine serum albumin, were found to stick to the surface of pepstatin A filaments, ribbons and sheets. Independent evidence for direct association of pepstatin A with intermediate filament subunit proteins was provided not only by electron microscopy but also by UV difference spectra. Pepstatin A loses its ability to inhibit the aspartyl protease of the human immunodeficiency virus type 1 following polymerization into the higher order structures described here. The amazing fact that pepstatin A can spontaneously self-associate to form very large polymers seems to be a more rare event for such small peptides. The other examples of synthetic or naturally occurring oligopeptides discussed in this review which are able to polymerize into higher order structures possess a common property, their hydrophobicity, often manifested by clusters of valine or isoleucine residues.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pepstatin A: polymerization of an oligopeptide. 805 47

The human immunodeficiency virus (HIV-1), associated with the AIDS (acquired immunodeficiency syndrome) epidemic, encodes an aspartyl protease that is essential for polyprotein processing in the virus (Navia et al., 1989). It has been demonstrated that inactivation of the protease either catalytically or by an inhibitor prevents infectious virion formation (Kohl et al., 1988; Darke et al., 1989). The acquired knowledge of key molecular interactions occurring between inhibitors and aspartyl proteases, as well as the structural similarities between HIV-1 protease and human renin was used to rationally select candidates for HIV-1 screening from the pool of analogs designed as renin inhibitors. A minimal number of chosen compounds were tested in an HIV-1 protease assay system. Two structurally novel peptides emerged as potent enzymatic protease inhibitors. This study highlights the selection process and characterizes the antiviral properties of the two novel analogs.
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PMID:Characterization of two structurally novel HIV-1 protease inhibitors identified by rational selection. 831 22

The Moloney murine leukemia virus (Mo-MuLV) protease has been cloned into the prokaryotic expression vector pGEX-2T, expressed in fusion with the glutathione S-transferase from Schistosoma japonicum, and purified to apparent homogeneity after thrombin cleavage of the chimeric protein. The purified protease showed maximum activity at pH 6.0 and was inhibited by several aspartyl protease inhibitors, found to be active toward the human immunodeficiency virus-1 (HIV-1) protease. Peptides representing maturation cleavage sites in Gag and Gag-Pol polyproteins were accurately cleaved by the recombinant protease, and kinetic parameters have been determined. In addition, oligopeptides mimicking the cleavage site found in the transmembrane protein and leading to the formation of p15E and p2E were also hydrolyzed at the expected position. The Mo-MuLV protease appears to be more closely related to the HIV-1 protease than to the mouse mammary tumor virus enzyme, based on its substrate specificity and sensitivity to aspartyl protease inhibitors.
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PMID:Moloney murine leukemia virus protease: bacterial expression and characterization of the purified enzyme. 837 34

Recent improvements in the management of people living with human immunodeficiency virus (HIV) disease in the United States have led to remarkable reductions in HIV-related morbidity and mortality. The Centers for Disease Control and Prevention recently reported substantial reductions in acquired immunodeficiency syndrome (AIDS)-related opportunistic infections and conditions, including HIV-related wasting. These achievements followed the introduction of the new class of antiretroviral therapies, the aspartyl protease inhibitors, and their use in combination with nucleoside inhibitors in so-called highly active antiretroviral therapies. In an effort to provide guidance for clinicians in HIV care, the Office of AIDS Research, United States Department of Health and Human Services recently convened a panel of experts to set clinical practice guidelines for the use of antiretroviral therapy in adults and adolescents. This article summarizes the new standard of care for the use of HIV therapies. It also reviews recent data suggesting that combination therapy has altered the natural history of HIV infection and has reduced the incidence of HIV-related nutritional disturbances and wasting.
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PMID:Current antiretroviral therapy and its impact on human immunodeficiency virus-related wasting. 962 90

Highly active antiretroviral therapy that includes human immunodeficiency virus (HIV) aspartyl protease inhibitors (PIs) causes a decline in the incidence of some opportunistic infections in AIDS, and this decline is currently attributed to the restoration of specific immunity. The effect of two PIs (indinavir and ritonavir) on the enzymatic activity of a secretory aspartyl protease (Sap) of Candida albicans (a major agent of mucosal disease in HIV-infected subjects) and on growth and experimental pathogenicity of this fungus was evaluated. Both PIs strongly (>/=90%) and dose dependently (0.1-10 microM) inhibited Sap activity and production. They also significantly reduced Candida growth in a nitrogen-limited, Sap expression-dependent growth medium and exerted a therapeutic effect in an experimental model of vaginal candidiasis, with an efficacy comparable to that of fluconazole. Thus, besides the expected immunorestoration, patients receiving PI therapy may benefit from a direct anticandidal activity of these drugs.
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PMID:In vitro and in vivo anticandidal activity of human immunodeficiency virus protease inhibitors. 1112 Sep 36

The role that lipids may play in enveloped viruses is reviewed. Small lipid molecules can influence retrovirus binding to cell receptors, plasma membrane fusion, and transcription. Palmitoylation following myristoylation of viral glycoproteins is required at the transmembrane level for signal transduction as well as for virion budding and maturation. Cholesterol, ether lipids, phospholipids, platelet-activating factor, phosphatidic acids, diacylglycerols, and several analogs and derivatives influence human immunodeficiency virus (HIV) activity; when conjugated with inhibitors of the viral reverse transcriptase (RT) or aspartyl protease these compounds increase drug effectiveness. On the other hand, L-carnitine, in association with the mitochondrial cardiolipins, inhibits myopathy due to continued prescription of drugs [AZT (zidovudine), ddl (didanoside), or ddC (zalcitabine)], and the redox couple of alpha-lipoic-dihydrolipoic acid prevents production of the reactive oxygen species that trigger apoptosis of infected cells, with sphingomyelin breakdown to ceramides. Retroviral infection induces a shift from phospholipid to neutral fat synthesis in host cells, and a long antiviral, i.e., antiprotease, treatment may lead to lipodystrophy. Multitherapy involving lipids and their analogs in association with anti-RT and antiproteases might enhance the inhibition of growth and proliferation of retroviruses.
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PMID:Lipids and retroviruses. 1075 41

The protease (PR) from human immunodeficiency virus (HIV) is essential for viral replication: this aspartyl protease, active only as a dimer, is responsible for cleavage of the viral polyprotein precursors (Gag and Gag-Pol), to release the functional mature proteins. In this work, we have studied the structure-function relationships of the HIV PR by combining a genetic test to detect proteolytic activity in Escherichia coli and a bacterial two-hybrid assay to analyze PR dimerization. We showed that a drug-resistant PR variant isolated from a patient receiving highly active antiretroviral therapy is impaired in its dimerization capability and, as a consequence, is proteolytically inactive. We further showed that the polypeptide regions adjacent to the PR coding sequence in the Gag-Pol polyprotein precursor, and in particular, the transframe polypeptide (TF), located at the N terminus of PR, can facilitate the dimerization of this variant PR and restore its enzymatic activity. We propose that the TF protein could help to compensate for folding and/or dimerization defects in PR arising from certain mutations within the PR coding sequence and might therefore function to buffer genetic variations in PR.
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PMID:Human immunodeficiency virus (HIV) type 1 transframe protein can restore activity to a dimerization-deficient HIV protease variant. 1285 90

The human immunodeficiency virus (HIV) has been shown to be the causative agent for AIDS. The HIV virus encodes for a unique aspartyl protease that is essential for the production of enzymes and proteins in the final stages of maturation. Protease inhibitors have been useful in combating the disease. The inhibitors incorporate a variety of isosteres including the hydroxyethylurea at the protease cleavage site. We have shown that the replacement of t-butylurea moiety by benzothiazolesulfonamide provided inhibitors with improved potency and antiviral activities. Some of the compounds have shown good oral bioavailability and half-life in rats. The synthesis of benzothiazole derivatives led us to explore other heterocycles. During the course of our studies, we also developed an efficient synthesis of benzothiazole-6-sulfonic acid via a two-step procedure starting from sulfanilamide.
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PMID:Discovery of novel benzothiazolesulfonamides as potent inhibitors of HIV-1 protease. 1455 92


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