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)

The purpose of this presentation is to invite consideration by the research community of the hypothesis that sialidase, a virulence factor of Streptococcus pneumoniae (pneumococcus) and most other opportunistic co-infectious agents associated with HIV infection, advances progression of HIV infection to neuro-AIDS.
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PMID:Pneumococcus virulence factor sialidase: a new direction in neuro-AIDS research? 1474 24

Influenza virus infection can cause severe complications in human immunodeficiency virus type-1 (HIV-1)-infected individuals leading to an increased risk of complications and death compared to that seen in uninfected individuals. We assessed the capacity of influenza virus (Flu) to modulate transcription of the HIV-1 long terminal repeat (LTR) in human CD4+ T cells. We found that Flu is able to promote expression of both the transiently transfected and stably integrated HIV-1 LTR-driven reporter gene. Experiments performed with Arthrobacter-derived neuraminidase and ammonium chloride revealed that Flu-dependent activation of HIV-1 transcription required an intimate contact between Flu and the target cell and efficient entry of Flu inside human CD4+ T cells. Amplification of a Flu-specific mRNA by RT-PCR indicated that human T cells were indeed productively infected with Flu. Virus preparations rendered noninfectious after UV irradiation could no longer upregulate HIV-1 LTR activity. Furthermore, experiments conducted with wild type and NF-kappaB-mutated HIV-1 LTR-directed reporter vectors suggested that the positive action of Flu on HIV-1 LTR activity was mediated through the induction of NF-kappaB. Our data show that fully competent Flu can lead to NF-kappaB-dependent activation of HIV-1 transcription in CD4+ T cells.
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PMID:Influenza virus activates human immunodeficiency virus type-1 gene expression in human CD4-expressing T cells through an NF-kappaB-dependent pathway. 1563 53

Establishment of selective antiviral chemotherapy has achieved dramatic improvement of the prognosis of several viral infections. It has been considered for a long time that, unlike bacterial infections, viral diseases cannot be successfully treated with chemotherapeutic agents, since viral replication mostly depends on the host-cellular machinery. In fact, some compounds were reported to inhibit viral replication even in the 1950s and 1960s, yet they were also quite toxic to the host cells. The first antiviral compound that strongly inhibits viral replication without affecting the uninfected cells is the anti-herpes agent acyclovir (ACV), which was discovered in the 1970s. Furthermore, in the 1980s, the world-wide epidemic of AIDS caused by human immunodeficiency virus type 1 (HIV-1) infection has dramatically accelerated the development of new antiviral agents. At present, most of the effective antivirals are targeted at virus-specific enzymes, such as ACV for herpes virus thymidine kinase, zidovudine for HIV-1 reverse transcriptase, squinavir for HIV-1 protease, and oseltamivir for neuraminidase of influenza virus. These agents can be administered systemically without serious side effects. However, several drawbacks, including delayed toxicity and drug-resistance, are associated with long-term treatment with several antiviral agents mostly in highly active antiretroviral therapy for HIV-1 infection. Thus, it seems still mandatory to continue the search for more effective and less toxic compounds against various viral infections.
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PMID:[Advances in antiviral chemotherapy]. 1630 32

A method is presented for enumerating a large number of isosteric analogues of a ligand from a known protein-ligand complex structure and then rapidly calculating an estimate of their binding energies. This approach takes full advantage of the observed crystal structure, by reusing the atomic co-ordinates determined experimentally for one ligand, to approximate those of similar compounds that have approximately the same shape. By assuming that compounds with similar shapes adopt similar binding poses, and that entropic and protein flexibility effects are approximately constant across such an isosteric series ("the frozen ligand approximation"), it is possible to order their binding affinities relatively accurately. Additionally, the constraint that the atomic coordinates are invariant allows for a dramatic simplification in the Poisson-Boltzmann method used to calculation the electrostatic component of the binding energy. This algorithmic improvement allows for the calculation of tens of thousands of binding energies per second for drug-like molecules, enabling this technique to be used in screening large virtual libraries of isosteric analogues. Most significantly, this procedure is shown to be able to reproduce SAR effects of subtle medicinal chemistry substitutions. Finally, this paper reports the results of the proposed methodology on seven model systems; dihydrofolate reductase, Lck kinase, ribosome inactivating protein, L: -arabinose binding protein, neuraminidase, HIV-1 reverse transcriptase and COX-2.
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PMID:Electrostatic evaluation of isosteric analogues. 1684 6

Oligosaccharide processing enzymes such as glycosidases and glycosyltransferases are important classes of biocatalysts involved in synthesising specific oligosaccharide structures on proteins and lipids. These enzymes are known to be involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins, lysosomal catabolism of glycoconjugates and inter-cellular recognition events. Inhibition of these enzymes can disrupt biosynthesis of oligosaccharides, thus interfering in all of these processes. Hence, "glyco-enzyme" inhibitors might have enormous therapeutic potential in many diseases such as viral infection, cancer and diabetes. This very important prospect has led to increasing interest and demand for these compounds. Interference in oligosaccharide processing is the basis for the anti-influenza neuraminidase inhibitors that have recently been marketed and also for the potential use of glycosidase inhibitors against HIV, Gaucher's disease, hepatitis, and cancer. Since a rational design and synthesis of inhibitors are often extremely difficult due to the limited information regarding the structure of the active site, combinatorial approaches are particularly promising. This review will focus on synthetic efforts for the preparation of combinatorial libraries of glyco-enzyme inhibitors.
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PMID:Combinatorial approaches to iminosugars as glycosidase and glycosyltransferase inhibitors. 1701 77

Bacterial vaginosis (BV) is particularly common in black women, and in Nigeria it is often caused by Mycoplasma, as well as Atopobium, Prevotella and Gardnerella sp. Antimicrobial metronidazole oral therapy is poorly effective in eradicating the condition and restoring the Lactobacillus microbiota in the vagina. In this study, 40 women diagnosed with BV by discharge, fishy odor, sialidase positive test and Nugent Gram stain scoring, were randomized to receive either two dried capsules containing Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 each night for 5 days, or 0.75% metronidazole gel, applied vaginally twice a day (in the morning and evening). Follow-up at day 6, 15 and 30 showed cure of BV in significantly more probiotic treated subjects (16, 17 and 18/20, respectively) compared to metronidazole treatment (9, 9 and 11/20: P=0.016 at day 6, P=0.002 at day 15 and P=0.056 at day 30). This is the first report of an effective (90%) cure of BV using probiotic lactobacilli. Given the correlation between BV and HIV, and the high risk of the latter in Nigeria, intravaginal use of lactobacilli could provide women with a self-use therapy, similar to over-the-counter anti-yeast medication, for treatment of urogenital infections.
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PMID:Clinical study comparing probiotic Lactobacillus GR-1 and RC-14 with metronidazole vaginal gel to treat symptomatic bacterial vaginosis. 1704 32

A new GRID-based method for scaffold hopping (SHOP) is presented. In a fully automatic manner, scaffolds were identified in a database based on three types of 3D-descriptors. SHOP's ability to recover scaffolds was assessed and validated by searching a database spiked with fragments of known ligands of three different protein targets relevant for drug discovery using a rational approach based on statistical experimental design. Five out of eight and seven out of eight thrombin scaffolds and all seven HIV protease scaffolds were recovered within the top 10 and 31 out of 31 neuraminidase scaffolds were in the 31 top-ranked scaffolds. SHOP also identified new scaffolds with substantially different chemotypes from the queries. Docking analysis indicated that the new scaffolds would have similar binding modes to those of the respective query scaffolds observed in X-ray structures. The databases contained scaffolds from published combinatorial libraries to ensure that identified scaffolds could be feasibly synthesized.
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PMID:SHOP: scaffold HOPping by GRID-based similarity searches. 1748 78

There are virtually no antiviral drugs available for the treatment of infections with RNA viruses. This is particularly worrisome since most of the highly pathogenic and emerging viruses are, and will likely continue to be, RNA viruses. These viruses can cause acute, severe illness, including severe respiratory disease, hemorrhagic fever and encephalitis, with a high case fatality rate. It is important to have potent and safe drugs at hand that can be used for the treatment or prophylaxis of such infections. Drugs approved for the treatment of RNA virus infections (other than HIV) are the influenza M2 channel inhibitors, amantadine and rimantadine; the influenza neuraminidase inhibitors, oseltamivir and zanamivir, and ribavirin for the treatment of infections with respiratory syncytial virus and hepatitis C virus. The molecular mechanism(s) by which ribavirin inhibits viral replication, such as depletion of intracellular GTP pools and induction of error catastrophe, may not readily allow the design of analogues that are more potent/selective than the parent drug. Highly pathogenic RNA viruses belong to a variety of virus families, each having a particular replication strategy, thus offering a wealth of potential targets to selectively inhibit viral replication. We here provide a non-exhaustive review of potential experimental strategies, using small molecules, to inhibit the replication of several RNA viruses. Other approaches, such as the use of interferon or other host-response modifiers, immune serum or neutralizing antibodies, are not addressed in this review.
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PMID:Molecular strategies to inhibit the replication of RNA viruses. 1831 69

In this study, we have generated and characterized an avian influenza H5N1 hemagglutinin (HA), neuraminidase (NA) and M2 ion channel pseudotyped HIV-based vector system (HaNaM-pseudotyped HIV vector). The cleavage site of the HA protein was modified to necessitate trypsin-dependent maturation of the glycoprotein. HA, NA and M2 were efficiently incorporated in HIV vector particles which could transduce different cell lines in a trypsin-dependent manner. Results also showed that the presence of avian influenza M2 and NA proteins maximized both vector production and transduction and that transduction was highly sensitive to the specific NA inhibitor oseltamivir (Tamiflu). H5N1 HaNaM-pseudotyped HIV vector system was also adapted for cell-based high throughput screening of drug candidates against influenza virus infection, and its high sensitivity to the specific oseltamivir validates its potential utility in the identification of new influenza inhibitors. Overall, the trypsin-dependent H5N1-pseudotyped HIV vector can mimic avian influenza virus infection processes with sufficient precision to allow for the identification of new antivirals and to study avian influenza virus biology in a lower biosafety level laboratory environment.
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PMID:Characterization of a trypsin-dependent avian influenza H5N1-pseudotyped HIV vector system for high throughput screening of inhibitory molecules. 1835 97

Among the RNA viruses, other than the retroviruses (that is, HIV), which are dealt with separately in the current FactFile, the most important targets for the development of antiviral agents at the moment are the orthomyxoviruses (that is, influenza), the hepaciviruses (that is, hepatitis C virus [HCV]) and, to a lesser extent, the picornaviruses. Although the uncoating inhibitors amantadine and rimantadine were the first known inhibitors of influenza A, the neuraminidase inhibitors oseltamivir, zanamivir and peramivir have now become the prime antiviral drugs for the treatment of influenza A and B virus infections. For HCV infections, standard treatment consists of the combination of pegylated interferon-alpha with ribavirin, but several other antivirals targeted at specific viral functions such as the HCV protease and/ or polymerase may be expected to soon take an important share of this important market. Still untapped is the potential of a variety of uncoating inhibitors, as well as protease and/or polymerase inhibitors against the wide spectrum of picornaviruses. While ribavirin has been available for 35 years as a broad-spectrum anti-RNA virus agent, relatively new and unexplored is favipiravir (T-705) accredited with activity against influenza as well as flaviviruses, bunyaviruses and arenaviruses.
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PMID:Antiviral Chemistry & Chemotherapy's current antiviral agents FactFile 2008 (2nd edition): RNA viruses. 1872 41


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