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)

Inhibitors of myristoylation and analogues of myristic acid inhibit the replication of some retroviruses including human immunodeficiency virus, but no studies with other virus families have been reported. We have shown that replication of varicella-zoster virus (VZV) in tissue is inhibited by DL-2-hydroxymyristic acid at concentrations similar to those required for inhibition with acyclovir. Protein synthesis is not inhibited, but protein myristoylation is non-specifically reduced. Despite this lack of specificity, DL-2-hydroxymyristic acid inhibits VZV replication without apparent cytotoxicity. This is in agreement with our earlier suggestion that non-specific inhibitors of myristoylation could have antiviral effects without toxicity to cells due to the stability of cellular myristoylproteins. This supports suggestions that myristoylation inhibitors have potential as antiviral drugs against the many viruses that produce myristoylproteins.
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PMID:Inhibition of varicella-zoster virus replication by an inhibitor of protein myristoylation. 838 1

To obtain a better understanding of the processes of assembly and morphogenesis of simian immunodeficiency virus (SIV), recombinant vaccinia viruses containing regions of the gag-pol open reading frame were constructed and their intracellular expression as well as the ability of the Gag polypeptides to be released into the culture medium as constituents of virus-like particles were studied. Biochemical and electron microscopy analyses of cells infected with a recombinant expressing only the SIV matrix (MA) domain of the Gag polyprotein (v-p17 gag) showed that this protein self-assembles into 100-nm virus-like particles which are released into the culture medium. Interestingly, coexpression of SIV MA and Env proteins resulted in incorporation of gp120 and gp41 proteins into the recombinant p17-made particles. In addition when a positively charged domain of SIV MA (residues 26-33), which is highly conserved among all HIV and SIV MA proteins, was mutated into an acidic region, particle release was abolished without affecting protein expression, processing, or stability. Further characterization of the phenotype of this mutant by electron microscopy indicated that this mutant was blocked at the stage of assembly. These results suggest that SIV MA protein, along with its function in myristic acid-mediated membrane targeting, has intrinsic information for self-assembly as well as incorporation of viral Env glycoproteins into particles.
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PMID:Assembly of the matrix protein of simian immunodeficiency virus into virus-like particles. 850 72

During retrovirus assembly, Gag proteins bind to the inner leaflet of the plasma membrane to initiate the budding process. The molecular basis of this protein-lipid interaction is poorly understood. For the human, immunodeficiency virus type 1 Gag protein, we recently reported that the membrane-binding domain resides within the N-terminal 31 amino acids and consists of two components: myristate and a cluster of basic residues, which together promote membrane binding in vitro and budding in vivo (W. Zhou, L. J. Parent, J. W. Wills, and M. D. Resh, J. Virol. 68:2556-2569, 1994). The positively charged residues associate electrostatically with acidic phospholipids to stabilize membrane binding, while myristate provides membrane-binding energy via hydrophobic interactions. Here we demonstrate that the human immunodeficiency virus type 1 Gag membrane-binding domain can fully replace the membrane-targeting function of the N-terminal 100 residues of the non-myristylated Rous sarcoma virus (RSV) Gag protein. To further explore the importance of myristate and basic residues in membrane binding, we developed a gain-of-function assay whereby budding was restored to defective mutants of RSV Gag. Detailed mutational analysis revealed that the position, number, and context of charged residues are crucial to budding. Myristate provides additional membrane-binding energy, which is critical when a Gag protein is near the threshold of stable membrane association. Finally, viruses with altered matrix (MA) proteins that are noninfectious, even though they produce particles with high efficiency, were identified. Thus, we present the first evidence that the RSV MA sequence plays two distinct roles, membrane binding during particle assembly and a second, as yet undefined function required for viral infectivity.
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PMID:Evidence for a second function of the MA sequence in the Rous sarcoma virus Gag protein. 855 59

A series of oxaanalogs of myristic acid were synthesized and tested for antiviral activity in MT4 cells infected with human immunodeficiency virus 1 (HIV-1). The synthesized acids have no toxic effect on uninfected MT4 cells at a concentration of 100 microM. 14,14,14-Trifluoro-12-oxatetradecanoic acid substantially (by 75%) inhibits the reproduction of HIV-1. Other compounds synthesized, (7Z)-13-, (9Z)-13-, and (7Z)-11-oxatetradecenoic acids, exhibit no antiviral effect.
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PMID:[A new oxa-analog of myristic acid, suppressing replication of the human immunodeficiency virus]. 858 18

A group of myristic acid analogs, designed as alternative substrates for N-myristoyltransferase (NMT), were evaluated against human immunodeficiency virus (HIV), hepatitis B virus (HBV) and duck hepatitis B virus (DHBV) in vitro. Antiviral potency was increased when S or O was substituted for -CH2- in myristic acid and selectivity was affected by the presence and position of the heteroatoms and phenyl groups. A correlation was established among anti-HIV activity, Log P and Log D7.4 and between anti-HIV activity and carbonyl-heteroatom interatomic distances in the myristoyl analogs. 12-Thioethyldodecanoic acid 6 was moderately active (EC50 = 9.37 microM) against HIV-infected T4-lymphocytes (CEM-SS cell line), and it exhibited in vitro activity (EC50 = 17.8 microM) against HBV-producing 2.2.15 cell cultures derived from a human hepatoblastoma cell line (Hep G2). 12-Methoxydodecanoic acid 1 exhibited in vitro activity (EC50 = 20-30 microM) against hepatitis B in the HBV DNA-transfected 2.2.15 cell line. At a concentration of 10 microg/ml, none of the fatty acids significantly inhibited the replication of DHBV in infected hepatocytes.
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PMID:In vitro antiviral activities of myristic acid analogs against human immunodeficiency and hepatitis B viruses. 919 Oct 15

The interaction of the human immunodeficiency virus (HIV) Gag protein with the plasma membrane of a cell is a critical event in the assembly of HIV particles. The matrix protein region (MA) of HIV type 1 (HIV-1) Pr55Gag has previously been demonstrated to confer membrane-binding properties on the precursor polyprotein. Both the myristic acid moiety and additional determinants within MA are essential for plasma membrane binding and subsequent particle formation. In this study, we demonstrated the myristylation-dependent membrane interaction of MA in an in vivo membrane-binding assay. When expressed within mammalian cells, MA was found both in association with cellular membranes and in a membrane-free form. In contrast, the intact precursor Pr55Gag molecule analyzed in an identical manner was found almost exclusively bound to membranes. Both membrane-bound and membrane-free forms of MA were myristylated and phosphorylated. Differential membrane binding was not due to the formation of multimers, as dimeric and trimeric forms of MA were also found in both membrane-bound and membrane-free fractions. To define the requirements for membrane binding of MA, we analyzed the membrane binding of a series of MA deletion mutants. Surprisingly, deletions within alpha-helical regions forming the globular head of MA led to a dramatic increase in overall membrane binding. The stability of the MA-membrane interaction was not affected by these deletions, and no deletion eliminated membrane binding of the molecule. These results establish that myristic acid is a primary determinant of the stability of the Gag protein-membrane interaction and provide support for the hypothesis that a significant proportion of HIV-1 MA molecules may adopt a conformation in which myristic acid is hidden and unavailable for membrane interaction.
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PMID:Membrane binding of human immunodeficiency virus type 1 matrix protein in vivo supports a conformational myristyl switch mechanism. 926 80

The interaction of the human immunodeficiency virus type 1 (HIV-1) Pr55Gag molecule with the plasma membrane of an infected cell is an essential step of the viral life cycle. Myristic acid and positively charged residues within the N-terminal portion of MA constitute the membrane-binding domain of Pr55Gag. A separate assembly domain, termed the interaction (I) domain, is located nearer the C-terminal end of the molecule. The I domain is required for production of dense retroviral particles, but has not previously been described to influence the efficiency of membrane binding or the subcellular distribution of Gag. This study used a series of Gag-green fluorescent protein fusion constructs to define a region outside of MA which determines efficient plasma membrane interaction. This function was mapped to the nucleocapsid (NC) region of Gag. The minimal region in a series of C-terminally truncated Gag proteins conferring plasma membrane fluorescence was identified as the N-terminal 14 amino acids of NC. This same region was sufficient to create a density shift in released retrovirus-like particles from 1.13 to 1.17 g/ml. The functional assembly domain previously termed the I domain is thus required for the efficient plasma membrane binding of Gag, in addition to its role in determining the density of released particles. We propose a model in which the I domain facilitates the interaction of the N-terminal membrane-binding domain of Pr55Gag with the plasma membrane.
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PMID:The I domain is required for efficient plasma membrane binding of human immunodeficiency virus type 1 Pr55Gag. 952 90

For type-C and lentiviruses, including human immunodeficiency virus type 1 (HIV-1), the pathway of virus assembly remains poorly defined, and the assembly and budding of capsids are believed to occur simultaneously at the plasma membrane of the infected cell. We have now identified two putative HIV-1 assembly intermediate complexes in infected CD4+ T cells. The first of these intermediates, a detergent-resistant complex (DRC), was identified as a large oligomer that had a density of 1.10-1.13 g/ml and was primarily composed of Pr55Gag and Pr160Gag-Pol precursors. The other putative intermediate was a detergent-sensitive complex (DSC) with a density of 1.15-1.17 g/ml, which apparently represented the products of extensive proteolytic processing of both the Pr55Gag and Pr160Gag-Pol precursors. Both complexes could be distinguished from released mature virions as well as immature viral particles. Surprisingly, the formation of DRC was not dependent upon the myristylation at the N-terminus of the Gag proteins, a signal required for plasma membrane targeting and virus production. However, the myristic acid modification was essential for the formation of DSC. These data suggest that interactions between individual Gag molecules and between Gag and Gag-Pol precursors may occur before their targeting to the plasma membrane during HIV-1 assembly. However, formation of the late virus assembly complex and productive processing of Pr55Gag and Pr160Gag-Pol precursors apparently do not occur until these precursors are targeted to the plasma membrane.
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PMID:Identification and characterization of virus assembly intermediate complexes in HIV-1-infected CD4+ T cells. 952 17

5'-O-Myristoyl analogue derivatives of 3'-azido-2',3'-dideoxythymidine (AZT), designed as potential double-barrelled prodrugs to AZT and the myristic acid analogues, were synthesized. Their ability to protect CEM cells against human immunodeficiency virus (HIV)-induced cytopathogenicity was determined and structure-activity paradigms were developed. 3'-Azido-2',3'-dideoxy-5'-O-(4-oxatetradecanoyl)thymidine (EC50 = 1.4 nM) and 3'-azido-2',3'-deoxy-5'-O-(12-bromododecanoyl)thymidine (EC50 = 3.2 nM) were the most effective anti-HIV-1 agents, relative to AZT (EC50 = 10 nM). These myristoyl analogue derivatives were more lipophilic (calculated log P = 4.5-8.1 range) than the parent compound AZT (log P = 0.06), and a linear correlation between their log P and HPLC log retention times was observed. The ester cleavage half-lives (t1/2) for esters upon in vitro incubation with porcine liver esterase, rat plasma or rat brain homogenate was dependent on the steric bulk, and electronegative inductive effect of the alpha-substituent (H, Br, F), of the 5'-O-myristoyl analogue moiety. 3'-Azido-2',3'-dideoxy-5'-O-(11-(4-iodophenoxy) undecanoyl)-thymidine exhibited t1/2 values of 80.4, 3.7 and 150.0 min upon incubation with porcine liver esterase, rat plasma and rat brain homogenate, respectively.
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PMID:Synthesis, in vitro anti-human immunodeficiency virus structure-activity relationships and biological stability of 5'-O-myristoyl analogue derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) as potential prodrugs. 987 10

Negative factor (Nef) is a regulatory myristoylated protein of human immunodeficiency virus (HIV) that has a two-domain structure consisting of an anchor domain and a core domain separated by a specific cleavage site of the HIV proteases. For structural analysis, the HIV-1 Nef anchor domain (residues 2-57) was synthesized with a myristoylated and non-myristoylated N terminus. The structures of the two peptides were studied by1H NMR spectroscopy and a structural model was obtained by restrained molecular dynamic simulations. The non-myristoylated peptide does not have a unique, compactly folded structure but occurs in a relatively extended conformation. The only rather well-defined canonical secondary structure element is a short two-turn alpha-helix (H2) between Arg35 and Gly41. A tendency for another helical secondary structure element (H1) can be observed for the arginine-rich region (Arg17 to Arg22). Myristoylation of the N-terminal glycine residue leads to stabilization of both helices, H1 and H2. The first helix in the arginine-rich region is stabilized by the myristoylation and now contains residues Pro14 to Arg22. The second helix appears to be better defined and to contain more residues (Ala33 to Gly41) than in the absence of myristoylation. In addition, the hydrophobic N-terminal myristic acid residue interacts closely with the side-chain of Trp5 and thereby forms a loop with Gly2, Gly3 and Lys4 in the kink region. This interaction could possibly be disturbed by phosphorylation of a nearby serine residue, and modifiy the characteristic membrane interactions of the HIV-1 Nef anchor domain.
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PMID:Structure of the anchor-domain of myristoylated and non-myristoylated HIV-1 Nef protein. 1033 11


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