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)

Protein-protein recognition is the cornerstone of multiple cellular and pathological functions. Therefore, protein-protein interaction inhibition (2P2I) is endowed with great therapeutic potential despite the initial belief that 2P2I was refractory to small-molecule intervention. Improved knowledge of complex molecular binding surfaces has recently stimulated renewed interest for 2P2I, especially after identification of "hot spots" and first inhibitory compounds. However, the combination of target complexity and lack of starting compound has thwarted experimental results and created intellectual barriers. Here we combined virtual and experimental screening when no previously known inhibitors can be used as starting point in a structure-based research program that targets an SH3 binding surface of the HIV type I Nef protein. High-throughput docking and application of a pharmacophoric filter on one hand and search for analogy on the other hand identified drug-like compounds that were further confirmed to bind Nef in the micromolar range (isothermal titration calorimetry), to target the Nef SH3 binding surface (NMR experiments), and to efficiently compete for Nef-SH3 interactions (cell-based assay, GST pull-down). Initial identification of these compounds by virtual screening was validated by screening of the very same library of compounds in the cell-based assay, demonstrating that a significant enrichment factor was attained by the in silico screening. To our knowledge, our results identify the first set of drug-like compounds that functionally target the HIV-1 Nef SH3 binding surface and provide the basis for a powerful discovery process that should help to speed up 2P2I strategies and open avenues for new class of antiviral molecules.
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PMID:Protein protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein. 1804 18

Human immunodeficiency virus type 1 (HIV-1) transmembrane glycoprotein gp41 is targeted by broadly-reactive neutralizing antibodies 2F5 and 4E10, making it an attractive target for vaccine development. To better assess immunogenic properties of gp41, we generated five soluble glutathione S-transferase fusion proteins encompassing C-terminal 30, 64, 100, 142, or 172 (full-length) amino acids of gp41 ectodomain from M group consensus envelope sequence. Antibody responses in HIV-1-infected patients were evaluated using these proteins and overlapping peptides. We found (i) antibody responses against different regions of gp41 varied tremendously among individual patients, (ii) patients with stronger antibody responses against membrane-proximal external region exhibit broader and more potent neutralizing activity, and (iii) several patients mounted antibodies against epitopes that are near, or overlap with, those targeted by 2F5 or 4E10. These soluble gp41 fusion proteins could be an important source of antigens for future vaccine development efforts.
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PMID:Assessment of antibody responses against gp41 in HIV-1-infected patients using soluble gp41 fusion proteins and peptides derived from M group consensus envelope. 1806 50

Integration is an essential step in the retroviral lifecycle, and the lentiviral integrase binding protein lens epithelium-derived growth factor (LEDGF)/p75 plays a crucial role during human immunodeficiency virus type 1 (HIV-1) cDNA integration. In vitro, LEDGF/p75 stimulates HIV-1 integrase activity into naked target DNAs. Here, we demonstrate that this chromatin-associated protein also stimulates HIV-1 integration into reconstituted polynucleosome templates. Activation of integration depended on the LEDGF/p75-integrase interaction with either type of template. A differential requirement for the dominant DNA and chromatin-binding elements of LEDGF/p75 was however observed when using naked DNA versus polynucleosomes. With naked DNA, the complete removal of these N-terminal elements was required to abate cofactor function. With polynucleosomes, activation mainly depended on the PWWP domain, and to a lesser extent on nearby AT-hook DNA-binding motifs. GST pull-down assays furthermore revealed a role for the PWWP domain in binding to nucleosomes. These results are completely consistent with recent ex vivo studies that characterized the PWWP and integrase-binding domains of LEDGF/p75 as crucial for restoring HIV-1 infection to LEDGF-depleted cells. Our studies therefore establish novel in vitro conditions, highlighting chromatinized DNA as target acceptor templates, for physiologically relevant studies of LEDGF/p75 in lentiviral cDNA integration.
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PMID:Chromatinized templates reveal the requirement for the LEDGF/p75 PWWP domain during HIV-1 integration in vitro. 1817 27

Although acetaminophen overdose is a leading cause of fulminant hepatic failure, it is controversial whether therapeutic doses of acetaminophen can cause hepatotoxicity in alcoholics, especially those rendered most vulnerable by recent abstinence. We performed a randomized, triple-blind, parallel-group trial comparing sustained-release acetaminophen, 1300 mg orally q8h for 11 doses, against placebo. We enrolled chronic alcohol abusers (defined as >or= 6 drinks daily for >or= 6 weeks) who had discontinued alcohol consumption 12 to 72 hours prior to enrollment. Individuals with self-reported viral hepatitis, HIV or intravenous drug use, baseline AST or ALT >120 IU/L, or INR >1.5 were excluded. Hepatic function tests were drawn daily for 5 days. The primary outcome was change in serum alpha-GST, a sensitive experimental biomarker of hepatocellular injury; secondary outcomes were changes in serum AST, ALT, INR, and study withdrawal for a doubling of aminotransferases to >120 IU/L. Of 52 subjects randomized, 40 completed at least four days of intervention. Subjects receiving acetaminophen had 32% [95% CI 7%, 50%] and 29% [6%, 46%] lower serum alpha-GST concentrations on days 2 and 3, respectively, compared to placebo, but these differences disappeared by day 4. No subjects were withdrawn for safety reasons. In conclusion, therapeutic doses of sustained-release acetaminophen cause a measurable decrease in serum alpha-GST during the first days of abstinence from chronic alcohol use. While the mechanism is unclear, these observations do provide some reassurance that short courses of acetaminophen are unlikely to cause subclinical hepatocellular injury in recently abstinent alcoholics.
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PMID:Are recommended doses of acetaminophen hepatotoxic for recently abstinent alcoholics? A randomized trial. 1834 7

Insulin-like growth factor binding proteins (IGFBPs) have various IGF-independent cellular activities, including receptor-independent cellular uptake followed by transcriptional regulation, although mechanisms of cellular entry remain unclear. Herein, we focused on their receptor-independent cellular entry mechanism in terms of protein transduction domain (PTD) activity, which is an emerging technique useful for clinical applications. The peptides of 18 amino acid residues derived from IGFBP-3 and IGFBP-5, which involve heparin-binding regions, mediated cellular delivery of an exogenous protein into NIH3T3 and HeLa cells. Relative protein delivery activities of IGFBP-3/5-derived peptides were approximately 20-150% compared to that of the HIV-Tat peptide, a potent PTD. Heparin inhibited the uptake of the fusion proteins with IGFBP-3 and IGFBP-5, indicating that the delivery pathway is heparin-dependent endocytosis, similar to that of HIV-Tat. The delivery of GST fused to HIV-Tat was competed by either IGFBP-3 or IGFBP-5-derived synthetic peptides. Therefore, the entry pathways of the three PTDs are shared. Our data has shown a new approach for designing protein delivery systems using IGFBP-3/5 derived peptides based on the molecular mechanisms of IGF-independent activities of IGFBPs.
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PMID:Intracellular protein delivery activity of peptides derived from insulin-like growth factor binding proteins 3 and 5. 1860

Antioxidants significantly inhibit oxidative processes. The study seeks to determine the activity of endogenous antioxidants and CD4+ T-cell expression in HIV-serodiscordant-heterosexual partners. The case-control study had the following groups; A- (13 serodiscordant-seronegative subjects), B- (13 serodiscordant-seropositive subjects) and C/control- (13 healthy volunteers). CD4+ T-cell expression was determined using a FACScan (fluorescent activated cell sorting) flow cytometer. CAT (catalase), superoxide dismutase, glutathione peroxidase (GHPX) and glutathione S-transferase (GST) activities were assayed using spectrophotometer. The activities of SOD, GHPX, GST and CAT were significantly (P < 0.05) increased by 164.7% (0.090 +/- 0.032), 126% (662 +/- 96), 355.2% (22.023 +/- 1.4) and 119.1% (2.76 +/- 0.10), respectively, in group A when compared with B. The mean CD4+ T-cell (1348 +/- 142) showed a significant (P < 0.05) increase by 237% when compared with group B (400 +/- 182). Conversely, group B revealed a significant (P < 0.05) decrease in activity by 86.5% (CAT), 76.5% (SOD), 106.8% (GHPX) and 81.8% (GST) when compared with C. CD4+ T-cells in groups A and C (1390 +/- 190) did not show any significant decrease (3.11%). The antioxidant activity showed a positive correlation (P < 0.01, r = 0.89) with their respective CD4+ T-cells in groups A and C. Group B showed same positive correlation (P < 0.01, r = 0.76). These results show that high activity of endogenous antioxidants may have a protective role on CD4+ T-cells, which limits HIV infection.
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PMID:High plasma activity of endogenous antioxidants protect CD4+ T-cells in HIV-serodiscordant heterosexual partners in a Nigerian population. 1866 40

The small glutamine-rich tetratricopeptide repeat protein (SGT) belongs to a family of cochaperones that interacts with both Hsp70 and Hsp90 via the so-called TPR domain. Here, we present the crystal structure of the TPR domain of human SGT (SGT-TPR), which shows that it contains typical features found in the structures of other TPR domains. Previous studies show that full-length SGT can bind to both Vpu and Gag of human immunodeficiency virus type 1 (HIV-1) and the overexpression of SGT in cells reduces the efficiency of HIV-1 particle release. We show that SGT-TPR can bind Vpu and reduce the amount of HIV-1 p24, which is the viral capsid, secreted from cells transfected with the HIV-1 proviral construct, albeit at a lower efficiency than full-length SGT. This indicates that the TPR domain of SGT is sufficient for the inhibition of HIV-1 particle release but the N- and/or C-terminus also have some contributions. The SGT binding site in Vpu was also identified by using peptide array and confirmed by GST pull-down assay.
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PMID:Structural and functional characterization of human SGT and its interaction with Vpu of the human immunodeficiency virus type 1. 1875 57

The APOBEC3 cytidine deaminases are potent antiviral factors that restrict the replication of human immunodeficiency virus type 1 (HIV-1). In HIV-1-infected CD4+ T cells, the viral accessory protein Vif binds to APOBEC3G (A3G), APOBEC3F (A3F), and APOBEC3C (A3C) and targets these proteins for polyubiquitination by forming an E3 ubiquitin ligase with cullin 5. Previous studies identified regions of HIV-1 Vif, 40YRHHY44 and 12QVDRMR17, which are important for interaction with A3G and A3F, respectively, and showed that Vif residues 54 to 71 are sufficient for A3G binding. Here, we identify 69YXXL72 as a novel conserved motif in HIV-1 Vif that mediates binding to human A3G and its subsequent degradation. Studies on other APOBEC3 proteins revealed that Tyr69 and Leu72 are important for the degradation of A3F and A3C as well. Similar to A3F, A3C regulation is also mediated by Vif residues 12QVDRMR17. Simian immunodeficiency virus (SIV) Vif was shown to bind and degrade African green monkey A3G (agmA3G) and, unexpectedly, human A3C. The YXXL motif of SIVagm Vif was important for the inactivation of agmA3G and human A3C. Unlike HIV-1 Vif, however, SIVagm Vif does not require Tyr40 and His43 for agmA3G degradation. Tyr69 in the YXXL motif was critical for binding of recombinant glutathione S-transferase-Vif(1-94) to A3G in vitro. These results suggest that the YXXL motif in Vif is a potential target for small-molecule inhibitors to block Vif interaction with A3G, A3F, and A3C, and thereby protect cells against HIV-1 infection.
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PMID:Regulation of APOBEC3 proteins by a novel YXXL motif in human immunodeficiency virus type 1 Vif and simian immunodeficiency virus SIVagm Vif. 1910 96

Enfuvirtide (ENF) is currently the only FDA approved HIV fusion inhibitor in clinical use. Searching for more drugs in this category with higher efficacy and lower toxicity seems to be a logical next step. In line with this objective, a synthetic peptide with 36 amino acid residues, called Sifuvirtide (SFT), was designed based on the crystal structure of gp41. In this study, we show that SFT is a potent anti-HIV agent with relatively low cytotoxicity. SFT was found to inhibit replication of all tested HIV strains. The effective concentrations that inhibited 50% viral replication (EC(50)), as determined in all tested strains, were either comparable or lower than benchmark values derived from well-known anti-HIV drugs like ENF or AZT, while the cytotoxic concentrations causing 50% cell death (CC(50)) were relatively high, rendering it an ideal anti-HIV agent. A GST-pull down assay was performed to confirm that SFT is a fusion inhibitor. Furthermore, the activity of SFT on other targets in the HIV life cycle was also investigated, and all assays showed negative results. To further understand the mechanism of action of HIV peptide inhibitors, resistant variants of HIV-1(IIIB) were derived by serial virus passage in the presence of increasing doses of SFT or ENF. The results showed that there was cross-resistance between SFT and ENF. In conclusion, SFT is an ideal anti-HIV agent with high potency and low cytotoxicity, but may exhibit a certain extent of cross-resistance with ENF.
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PMID:Sifuvirtide, a potent HIV fusion inhibitor peptide. 1928 98

We previously reported that replacing HIV-1 nucleocapsid (NC) domain with SARS-CoV nucleocapsid (N) residues 2-213, 215-421, or 234-421 results in efficient virus-like particle (VLP) production at a level comparable to that of wild-type HIV-1. In this study we demonstrate that these chimeras are capable of packaging large amounts of human APOBEC3G (hA3G), and that an HIV-1 Gag chimera containing the carboxyl-terminal half of human coronavirus 229E (HCoV-229E) N as a substitute for NC is capable of directing VLP assembly and efficiently packaging hA3G. When co-expressed with SARS-CoV N and M (membrane) proteins, hA3G was efficiently incorporated into SARS-CoV VLPs. Data from GST pull-down assays suggest that the N sequence involved in N-hA3G interactions is located between residues 86 and 302. Like HIV-1 NC, the SARS-CoV or HCoV-229E N-associated with hA3G depends on the presence of RNA, with the first linker region essential for hA3G packaging into both HIV-1 and SARS-CoV VLPs. The results raise the possibility that hA3G is capable of associating with different species of viral structural proteins through a potentially common, RNA-mediated mechanism.
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PMID:APOBEC3G cytidine deaminase association with coronavirus nucleocapsid protein. 1934 73


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