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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The integrity of the vaginal mucosa is critical to protecting women from infection, particularly sexually transmitted diseases. For example, breakdown of the mucosa, including the cell lining and/or mucus layer, due to vaginal infections has been shown to increase the risk of HIV infection. There is considerable interest in the development of new topical microbicides for women; many of these topical agents contain polymers. One potential mechanism for altering the barrier properties of a three-dimensional fibrous gel, such as cervical mucus, to cell penetration is to alter the fiber structure. In previous studies, we have shown that addition of synthetic polymers, such as polyvinyl pyridine (PVP) and polyethylene glycol (PEG), modify the fiber structure and mechanical properties of human cervical mucus. Here we investigated the ability of peripheral blood monocytes to migrate through structurally altered mucus gels. Adding PVP to mucus increased both the average fiber spacing and the rate of random migration of monocytes; addition of PEG to mucus also caused an increased random migration rate, although changes in overall fiber spacing were not obvious. In both cases, the addition of small amounts of polymer to cervical mucus decreased the barrier property of mucus with respect to cell migration. This result raises questions about the safety of polymeric agents as ingredients in topical microbicides.
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PMID:The effect of synthetic polymers on the migration of monocytes through human cervical mucus. 1512 May 1

In recent years, significant progress has been made towards the chemotherapy (and prophylaxis) of HIV infections. This progress is situated at three different levels. (i) New anti-HIV drugs have been approved for clinical use and have entered the market: the virus entry inhibitor enfuvirtide (Fuzeon), the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (Emtriva), the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir disoproxil fumarate (Viread trade mark ) and the HIV protease inhibitor (PI) atazanavir (Reyataz trade mark ). (ii) Other compounds have proceeded through preclinical and/or clinical development: CXCR4 antagonists (i.e. AMD070), CCR5 antagonists (i.e. SCH-C), NRTIs (such as amdoxovir), NNRTIs (such as etravirine), integrase inhibitors (such as S-1360) and PIs (such as tipranavir). (iii) Yet other compounds, acting by novel mechanisms, have recently been identified as anti-HIV agents that seem worthy of further (pre)clinical development: cell receptor CD4 down-modulators (i.e. cyclotriazadisulfonamides), viral envelope gp120-binding agents such as plant lectins and glycopeptide antibiotics, HIV integrase inhibitors such as the pyranodipyrimidine V-165, and two new classes of compounds (i.e. N-aminoimidazoles and pyridine oxide derivatives) which seem to interfere with a post-integration, transcription transactivation event. Taken together, it is obvious that the approaches for the treatment of HIV infections in recent years have become both more diverse and more efficient.
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PMID:HIV-chemotherapy and -prophylaxis: new drugs, leads and approaches. 1518 46

Human CCR5 is a G-coupled receptor that binds to the envelope protein gp120 and CD4 and mediates the HIV-1 viral entry into the cells. The blockade of this binding by a small molecule receptor antagonist could lead to a new mode of action agent for HIV-1 and AIDS. Screening of natural product extracts led to the identification of anibamine (1), a novel pyridine quaternary alkaloid as a TFA salt, from Aniba sp.; ophiobolin C from fermentation extracts of fungi Mollisia sp.; and 19,20-epoxycytochalasin Q from Xylaria sp. Formation of the TFA salt of anibamine is plausibly an artifact of the isolation. The identity of the natural counterion is unknown. Anibamine.TFA competed for the binding of 125I-gp120 to human CCR5 with an IC50 of 1 microM. Ophiobolin C and 19,20-epoxycytochalasin Q exhibited binding IC50) values of 40 and 60 microM, respectively.
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PMID:Isolation and structure of antagonists of chemokine receptor (CCR5). 1521 90

In order to develop orally active CCR5 antagonists, we investigated 1-benzoxepine derivatives containing new polar substituents, such as phosphonate, phosphine oxide or pyridine N-oxide moieties, as replacements for the previously reported quaternary ammonium moiety. Among these compounds, the 2-(alpha-hydroxybenzyl)pyridine N-oxide 5e exhibited moderate CCR5 antagonistic activity and had an acceptable pharmacokinetic profile in rats. Subsequent chemical modification was performed and compound (S)-5f possessing the (S)-configuration hydroxy group was found to be more active than the (R)-isomer. Replacement of the 1-benzoxepine ring with a 4-methylphenyl group by a 1-benzazepine ring with a 4-[2-(butoxy)ethoxy]phenyl group enhanced the activity in the binding assay. In addition, introduction of a 3-trifluoromethyl group on the phenyl group of the anilide moiety led to greatly increased activity in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound (S)-5s showed the most potent CCR5 antagonistic activity (IC(50)=7.2 nM) and inhibitory effect (IC(50)=5.4 nM) in the fusion assay, together with good pharmacokinetic properties in rats.
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PMID:Orally active CCR5 antagonists as anti-HIV-1 agents 2: synthesis and biological activities of anilide derivatives containing a pyridine N-oxide moiety. 1525 2

In 1995, we discovered new antiherpetic antibiotics, called fattiviracins. The producing organism was classified as a strain belonging to Streptomyces microflavus. The strain produced at least 13 fattiviracin derivatives (FV-1 to FV-13). Fattiviracins were obtained as a white amorphous powder, and their molecular weights are in the range of 1400 to 1500. They are readily soluble in water, methanol, pyridine, and DMSO, but insoluble in other organic solvents. Fattiviracins have macrocyclic diesters formed by the binding of two trihydroxy fatty acids and two D-glucose residues in the molecule, and they can be divided into five families according to the length of the fatty acid moiety. Fattiviracins have potent activity against enveloped DNA viruses such as the herpes family, HSV-1, and VZV and enveloped RNA viruses such as influenza A and B viruses, and three strains of HIV-1, with EC(50) values on the order of a few micrograms per milliliter. The biosynthetic pathway of fattiviracins is also becoming clearer. Using bacitracin-resistant strains, enhanced and astringent production of fattiviracin was achieved. Fattiviracin FV-13, which has the longest fatty acid chains in the molecule, was dramatically enhanced by a C(55)-isoprenyl phosphate metabolism. In addition, we have screened various inhibitors of enzymes such as alkaline protease, glucosyltransferase, glucuronidase, phospholipase, deoxyribonuclease, DNA methyltransferase, and DNA topoisomerase. All the inhibitors we discovered are briefly summarized in this paper.
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PMID:[Metabolites produced by actinomycetes--antiviral antibiotics and enzyme inhibitors]. 1529 17

Synthesis of phosphoramidate protides of carbocyclic D- and L-2',3'-dideoxy-2',3'-didehydro-7-deazaadenosine by treatment of the nucleoside with phosphorochloridates in the presence of pyridine and t-BuMgCl is described. Several of these protides showed significantly improved antiviral potency over the parent nucleosides against both HIV and HBV.
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PMID:Phosphoramidate protides of carbocyclic 2',3'-dideoxy-2',3'-didehydro-7-deazaadenosine with potent activity against HIV and HBV. 1562 49

A novel protein, named BAS-AH, was purified and characterized from the skin of the toad Bufo andrewsi. BAS-AH is a single chain protein and the apparent molecular weight is about 63 kDa as judged by SDS-PAGE. BAS-AH was determined to bind heme (0.89 mol heme/mol protein) as determined by pyridine haemochrome analysis. Fifty percentage cytotoxic concentration (CC50) of BAS-AH on C8166 cells was 9.5 microM. However, at concentrations that showed little effect on cell viability, BAS-AH displayed dose dependent inhibition on HIV-1 infection and replication. The antiviral selectivity indexes (CC50/EC50) were 14.4 and 11.4, respectively, corresponding to the measurements of syncytium formation and HIV-1 p24 antigen expression. BAS-AH also showed an inhibitory effect on the activity of recombinant HIV-1 reverse transcriptase (IC50 = 1.32 microM). The N-terminal sequence of BAS-AH was determined to be NAKXKADVIGKISILLGQDNLSNIVAAM, which exhibited little identity with other known anti-HIV-1 proteins. BAS-AH is devoid of antibacterial, proteolytic, trypsin inhibitory activity, l-amino acid oxidase activity and catalase activity.
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PMID:A novel heme-containing protein with anti-HIV-1 activity from skin secretions of Bufo andrewsi. 1615 59

Pyridine N-oxide derivatives represent a new class of anti-HIV compounds for which some members exclusively inhibit HIV-1 RT, whereas other members act, additionally or alternatively, at a post-integrational event in the replicative cycle of HIV. A prototype pyridine N-oxide derivative, JPL-32, inhibited tumor necrosis factor alpha (TNF-alpha)-induced HIV-1 expression in latently HIV-1-infected OM-10.1 and U1 cells, which could be reversed by the addition of N-acetyl-L-cysteine (NAC). The reversal of the antiviral activity of JPL-32 by NAC suggested the possible role of a redox-sensitive factor as target of inhibition. Indeed, when nuclear extracts of TNF-alpha-stimulated OM-10.1 and U1 cells cultured in the presence of JPL-32 were analyzed by an electrophoretic mobility shift assay (EMSA), a dose-dependent inhibition of DNA binding of nuclear NF-kappaB was observed, which could be reversed by the addition of NAC. JPL-32 did not inhibit the release and subsequent degradation of IkappaBalpha, nor did JPL-32 affect the nuclear translocation of NF-kappaB. EMSA revealed that the inhibition of the NF-kappaB DNA binding activity by JPL-32 could be reversed by the addition of reducing agents such as dithiothreitol or beta-mercaptoethanol. Moreover, JPL-32 was able to directly oxidize the thiol groups on the purified p50 subunit of recombinant NF-kappaB. The oxidative modification of the thiol groups on NF-kappaB by JPL-32 could be ascribed to the intracellular pro-oxidant effect of JPL-32. Consequently, JPL-32 was able to increase the intracellular glutathione (GSH) levels and to induce apoptosis in a dose-dependent way.
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PMID:Pyridine N-oxide derivatives inhibit viral transactivation by interfering with NF-kappaB binding. 1643 40

Human Topoisomerase II is present in two isoforms, 170KDa alpha and 180KDa beta. Both the isoforms play a crucial role in maintenance of topological changes during DNA replication and recombination. It has been shown that Topoisomerase II activity is required for HIV-1 replication and the enzyme is phosphorylated during early time points of HIV-1 replication. In the present study, we have studied the molecular action of Topoisomerase II inhibitors, azalactone ferrocene (AzaFecp), Thiomorpholide amido methyl ferrocene (ThioFecp), and Ruthenium benzene amino pyridine (Ru(ben)Apy) on cell proliferation and also on various events of HIV-1 replication cycle. The Topoisomerase II beta over-expressing neuroblastoma cell line shows a higher sensitivity to these compounds compared to the Sup-T1 cell line. All the three Topoisomerase II inhibitors show significant anti-HIV activity at nanomolar concentrations against an Indian isolate of HIV-1(93IN101) in Sup-T1 cell line. An analysis of action of these compounds on proviral DNA synthesis at 5h of post-infection shows that they inhibit proviral DNA synthesis as well as the formation of pre-integration complexes completely. Further analysis, using polymerase chain reaction and western blot, showed that both the Topoisomerase II alpha and beta isoforms are present in the pre-integration complexes, suggesting their significant role in HIV-1 replication.
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PMID:A study of the topoisomerase II activity in HIV-1 replication using the ferrocene derivatives as probes. 1671 76

This communication details both the syntheses and biological evaluation of a novel class of HIV-1 integrase inhibitors. When the quinoline moiety is replaced with the quinoxoline moiety, the antiviral activity is significantly compromised. Similarly, introduction of imidazole to replace the pyridine ring is deleterious to the potency of the compound against the enzyme. Substitution at the 3-position of the pyridine has been investigated. The presence of the pyridine ring in the tricyclic core is preferred for antiviral activity against HIV integrase.
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PMID:Design, synthesis, and biological evaluation of novel tricyclic HIV-1 integrase inhibitors by modification of its pyridine ring. 1672 26


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