UMLS:C0019693 - FACTA Search

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)

Various poly(ethylene glycol)(PEG)-based prodrug conjugates of the HIV-1 protease inhibitor (PI) saquinavir (SQV) were prepared using several types of chemical groups potentially capable of modifying its pharmacokinetic properties. These prodrug conjugates included SQV-cysteine-PEG3400, SQV-cysteine-PEG3400-biotin, SQV-cysteine(R.I.CK-Tat9) [a cationic retro-inverso-cysteine-lysine-Tat nonapeptide]-PEG3400, and SQV-cysteine(R.I.CK(stearate)-Tat9)-PEG3400. SQV was linked to cysteine to form a releasable SQV-cysteine ester bond in all of the conjugates. The amino group of the cysteine moiety provided an attachment site for a slower-degrading amide bond with N-hydroxysuccinimide-activated forms of PEG- and PEG-biotin. Disulfide bonds were used to attach the cationic peptides, R.I.CK-Tat9 and R.I.CK(stearate)-Tat9 to the cysteine moiety in order to provide cell-specific release. An assay was established and validated for measuring the activity of SQV and other protease inhibitors in biological samples. In this assay, cleavage of an internally quenched fluorescent substrate, Arg-Glu(EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gly-Lys(DABCYL)-Arg by HIV-1 protease was inhibited by SQV in a dose-dependent manner at concentrations of 0.05-0.5 microM. All prodrug conjugates were shown to be inactive in this assay until the ester bond was cleaved and active SQV was released. The prodrug reconversion half-lives in 0.1 N HCl, phosphate-buffered saline (PBS) at pH 7.4 and in spiked plasma at 37 degrees C were 9, 14, and 0.9 h, respectively. The anti-HIV-1 activity (ED(50)) of the PEG-based SQV prodrug conjugates was evaluated in MT-2 cells using an MTT assay. The activity of conjugated SQV was reduced (ED(50) = 900 nM) for the PEG only conjugate, but restored with the addition of biotin (ED(50) = 125 nM), R.I.CK-Tat9 (ED(50) = 15 nM), and R.I.CK(stearate)-Tat9 (ED(50) = 62 nM) as compared to maximum achievable anti-HIV-1 activity (unconjugated SQV, control, ED(50) = 15 nM), suggesting enhanced cellular uptake of conjugates. Cytotoxicity (LD(50)) was assessed for all prodrug conjugates using non-HIV-1 infected cells and was found to be in the micromolar range. The difference between the LD(50) and ED(50) suggests a favorable therapeutic index for the prodrug conjugates. In conclusion, these promising initial results demonstrate that the reconversion of the conjugate prodrugs was complete and that active SQV was released. Since the major delivery advantages of PEG prodrug conjugates can only be observed in vivo, issues of reconversion and elimination half-lives in plasma will have to be further studied in an in vivo model. The current results also demonstrate that the protease inhibition assay is a simple yet effective bioanalytical tool that can be used to assess the release and anti-HIV-1 activity of HIV-1 PIs from their prodrug forms.
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PMID:Synthesis of poly(ethylene glycol)-based saquinavir prodrug conjugates and assessment of release and anti-HIV-1 bioactivity using a novel protease inhibition assay. 1554 99

Partial splenic embolization (PSE), a non-surgical treatment for hypersplenism, has also been reported to improve hepatic function. As severe thrombocytopaenia or leukopaenia contraindicate the use of combined therapy with pegylated interferons (PEG-IFNs) and ribavirin (RBV) in HCV-related cirrhosis, we evaluated, from July 2002 to October 2003, the safety and effectiveness of PSE as a procedure to allow therapy for HCV in three Child-Pugh class B cirrhotic patients with hypersplenism and HIV co-infection. HCV genotypes were 1b (n=2) and 3a (n=1). Severe thrombocytopaenia (in all) and leukopaenia (in two) precluded therapy for HCV. PSE was successfully performed in all with a mean infarcted area of 80%, leading to a significant increase in platelet and leukocyte counts that allowed therapy with weight-adjusted RBV and PEG-IFN-alpha-2b (patients 1 and 3) or 180 microg of PEG-IFN-alpha-2a (patient 2) 8 weeks after the procedure. Moderate pain, well controlled with conservative measures, followed PSE in 100% of cases, but during follow-up (mean 422 days) there were no infectious complications or liver decompensation episodes. Although preliminary, these results suggest the potential role of PSE in HIV/HCV-cirrhotic subjects with hypersplenism as a procedure to allow the use of combined PEG-IFN and RBV.
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PMID:Partial splenic embolization for the treatment of hypersplenism in cirrhotic HIV/HCV patients prior to pegylated interferon and ribavirin. 1565 61

Our understanding of the pathogenicity of hepatitis C virus (HCV) is based on patients infected chronically for >20 years. The lack of a suitable animal model, the narrow host range of the virus, and the protracted onset of liver disease induced by HCV have hampered advances in treatment. In spite of these problems, we identified patient and viral characteristics that predict responses to current therapies, including HCV genotype, viral load, body weight, age, liver histology, co-infection with HIV and treatment adherence and tolerance. Interferon (IFN) alpha was the first therapy for chronic HCV infection. The combination of IFN plus ribavirin increases sustained virological response rates compared with IFN alone. Two pegylated IFNs have been developed and are widely approved for the treatment of chronic hepatitis C: peginterferon alpha-2a (40 KD), and pegylated IFN alpha-2b (12 KD). These products have reduced systemic clearance, prolonged half-lives and reduced antigenicity compared with conventional IFN. The reduced clearance results in sustained plasma levels of the drug and allows for once-weekly dosing. Pegylated IFN alpha-2b (12 KD) has a small, linear polyethylene glycol (PEG) moiety and has an intermediate duration of activity; peginterferon alpha-2a (40 KD) incorporates a large, branched-chain PEG moiety and has a longer half-life than both conventional IFN alpha and pegylated IFN alpha-2b (12 KD). The combination of a pegylated IFN plus ribavirin significantly increases sustained virological response rates compared with conventional IFN plus ribavirin in patients with chronic hepatitis C and is now recognized as the standard of care for these patients.
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PMID:Therapeutic modalities in hepatitis C: challenges and development. 1565 43

Considering that HIV-1 accumulates and replicates actively within lymphoid tissues, any strategy that will decrease viral stores in these tissues might be beneficial to the infected host. Follicular dendritic cells (FDC), B lymphocytes, antigen-presenting cells like macrophages, and activated CD4(+) T cells are abundant in lymphoid tissues, and all express substantial levels of the HLA-DR determinant of the major histocompatibility complex class II (MHC-II). Monocyte-derived macrophages, which are also CD4(+) and express HLA-DR, are considered to be the most frequent hosts of HIV-1 in tissues of infected individuals. This chapter describes a method for the generation of sterically stabilized immunoliposomes grafted with anti-HLA-DR antibodies that allows efficient delivery of drugs to lymphoid tissues. The method first involves the production of murine HLA-DR (clone Y-17, IgG(2b)) and human HLA-DR (clone 2.06, IgG(1)) antibodies from hybridomas in mice and their purification from ascites fluids. This step is followed by the production of Fab' fragments of antibodies 2.06 and Y-17 that are grafted at the surface of sterically stabilized immunoliposomes instead of the complete IgG to reduce their immunogenicity. The preparation of sterically stabilized liposomes, the composition of which allows an efficient entrapment and retention of several drugs, by the method of thin lipid film hydratation followed by extrusion through polycarbonate membranes is then described. This step is followed by the removal of unencapsulated drug, when present, by low-speed centrifugation of the liposomal preparation through a Sephadex G-50 column. These liposomes contain a fixed amount of poly(ethylene glycol) chain terminated by a maleimide reactive group for the coupling of Fab' fragments. The procedure for the coupling of Fab' fragments at the surface of sterically stabilized liposomes and the removal of uncoupled fragments of antibodies is described. In vitro binding studies of sterically stabilized immunoliposomes to cell lines expressing different surface levels of the mouse or human HLA-DR determinant of MHC-II demonstrate that these liposomes are very specific. When compared with conventional liposomes, the subcutaneous administration in the upper back, below the neck, of mice of anti-HLA-DR immunoliposomes resulted in a 2.9 and 1.6 times greater accumulation in the cervical and brachial lymph nodes, respectively. The use of sterically stabilized immunoliposomes increases 2 to 4.6 times the concentration of liposomes in all tissues, with a peak accumulation at 240 h in brachial, inguinal, and popliteal lymph nodes and at 360 h or greater in cervical lymph nodes. A single bolus injection of indinavir given subcutaneously to mice results in no significant drug levels in lymphoid organs. Most of the injected drug accumulates in the liver and is totally cleared within 24 h postadministration. In contrast, sterically stabilized immunoliposomes are very efficient in delivering high concentrations of indinavir to lymphoid tissues for at least 15 days postinjection. The drug accumulation in all tissues leads to a 21- to 126-fold increased accumulation when compared with the free agent. Anti-HLA-DR immunoliposomes containing indinavir are as efficient as the free agent in inhibiting HIV-1 replication in PM1 cells that express high levels of cell surface HLA-DR. Sterically stabilized anti-HLA-DR immunoliposomes mostly accumulate in the cortex in which follicles (B cells and FDCs) are located, and in parafollicular areas in which T cells, interdigitating dendritic cells, and other accessory cells are abundant. The delivery of drugs in this area of the lymph nodes could represent a convenient strategy to inhibit more efficiently HIV-1 replication. Although the method described in this chapter is specific to the coupling of anti-HLA-DR antibodies, any antibody fragment or peptide specific for an antigen present in relatively large quantities at the surface of lymphoid cells, that is anchored to the surface of sterically stabilized liposomes with an appropriate coupling method, can be used to concentrate drugs within target tissues and improve the therapeutic effect of drugs.
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PMID:Lymphoid tissue targeting of anti-HIV drugs using liposomes. 1572 90

Hepatitis C virus (HCV) infects approximately 3 % of the global population and represents a major public health problem worldwide. Treatment of chronic hepatitis C is based on the combination of pegylated interferon alpha (PEG IFN) with ribavirin. With this treatment, sustained virological response is obtained in around 80% of patients infected with HCV genotype 2 or 3 and 50% of patients infected with HCV genotype 1. The most frequent adverse events are the flu-like syndrome and psychiatric disorders for PEG IFN, and anaemia for ribavirin; they need a careful follow-up. Determination of viral load and genotype is essential for the indication of therapy and the follow-up during treatment. Patients infected with HCV genotype 2 or 3 should be treated for 24 weeks. In patients infected with HCV genotype 1, a decrease in viral load by 2 log after 12 weeks of treatment (early virological response) is needed to take the decision to continue treatment, for a total duration of 48 weeks. A poor response to treatment is associated with host factors (age, alcohol consumption, cirrhosis) and viral factors (genotype 1, high viral load, co-infection with HBV or HIV). New therapeutic approaches should be based on the combination of PEG IFN and specific inhibitors of HCV replication to increase the rate of sustained response.
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PMID:[Treatment of hepatitis C]. 1591 15

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate, fluvastatin sodium, fondaparinux sodium; Gaboxadol, gamma-hydroxybutyrate sodium, gefitinib, gelclair, gemcitabine, gemfibrozil, glibenclamide, glyminox; Haloperidol, heparin sodium, HPV 16/HPV 18 vaccine, human insulin, human insulin; Icatibant, imatinib mesylate, indium 111 (111In) ibritumomab tiuxetan, infliximab, INKP-100, iodine (I131) tositumomab, IoGen, ipratropium bromide, ixabepilone; L-870810, lamivudine, lapatinib, laquinimod, latanoprost, levonorgestrel, licochalcone a, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, lorazepam, lovastatin; Maraviroc, maribavir, matuzumab, MDL-100907, melphalan, methotrexate, methylprednisolone, mitomycin, mitoxantrone hydrochloride, MK-0431, MN-001, MRKAd5 HIV-1 gag/pol/nef, MRKAd5gag, MVA.HIVA, MVA-BN Nef, MVA-Muc1-IL-2, mycophenolate mofetil; Nelfinavir mesilate, nesiritide, NSC-330507; Olanzapine, olmesartan medoxomil, omalizumab, oral insulin, osanetant; PA-457, paclitaxel, paroxetine, paroxetine hydrochloride, PCK-3145, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, perillyl alcohol, pexelizumab, pimecrolimus, pitavastatin calcium, porfiromycin, prasterone, prasugrel, pravastatin sodium, prednisone, pregabalin, prinomastat, PRO-2000, propofol, prostate cancer vaccine; Rasagiline mesilate, rhBMP-2/ACS, rhBMP-2/BCP, rhC1, ribavirin, rilpivirine, ritonavir, rituximab, Ro-26-9228, rosuvastatin calcium, rosuvastatin sodium, rubitecan; Selodenoson, simvastatin, sirolimus, sitaxsentan sodium, sorafenib, SS(dsFv)-PE38, St. John's Wort extract, stavudine; Tacrolimus, tadalafil, tafenoquine succinate, talaglumetad, tanomastat, taxus, tegaserod maleate, telithromycin, tempol, tenofovir, tenofovir disoproxil fumarate, testosterone enanthate, TH-9507, thalidomide, tigecycline, timolol maleate, tiotropium bromide, tipifarnib, torcetrapib, trabectedin, travoprost, travoprost/timolol, treprostinil sodium; Valdecoxib, vardenafil hydrochloride hydrate, varenicline, VEGF-2 gene therapy, venlafaxine hydrochloride, vildagliptin, vincristine sulfate, voriconazole, VRX-496, VX-385; Warfarin sodium; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, zidovudine.
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PMID:Gateways to clinical trials. 1608 22

The fusion peptides of HIV and influenza virus are crucial for viral entry into a host cell. We report the membrane-perturbing and structural properties of fusion peptides from the HA fusion protein of influenza virus and the gp41 fusion protein of HIV. Our goals were to determine: 1), how fusion peptides alter structure within the bilayers of fusogenic and nonfusogenic lipid vesicles and 2), how fusion peptide structure is related to the ability to promote fusion. Fluorescent probes revealed that neither peptide had a significant effect on bilayer packing at the water-membrane interface, but both increased acyl chain order in both fusogenic and nonfusogenic vesicles. Both also reduced free volume within the bilayer as indicated by partitioning of a lipophilic fluorophore into membranes. These membrane ordering effects were smaller for the gp41 peptide than for the HA peptide at low peptide/lipid ratio, suggesting that the two peptides assume different structures on membranes. The influenza peptide was predominantly helical, and the gp41 peptide was predominantly antiparallel beta-sheet when membrane bound, however, the depths of penetration of Trps of both peptides into neutral membranes were similar and independent of membrane composition. We previously demonstrated: 1), the abilities of both peptides to promote fusion but not initial intermediate formation during PEG-mediated fusion and 2), the ability of hexadecane to compete with this effect of the fusion peptides. Taken together, our current and past results suggest a hypothesis for a common mechanism by which these two viral fusion peptides promote fusion.
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PMID:Properties and structures of the influenza and HIV fusion peptides on lipid membranes: implications for a role in fusion. 1618 90

Five new porphyrin-peptide conjugates bearing a nuclear localizing sequence SV40 or a fusogenic peptide (HIV-1Tat 40-60 or octa-arginine) linked by low molecular weight poly(ethylene glycol) have been synthesized. In vitro studies using human HEp2 cells show that the cellular uptake of the conjugates depends significantly on the nature and sequence of amino acids in the peptide and on the nature of the substituents on the porphyrin macrocycle. The fusogenic peptide sequences HIV-1Tat 40-60 and octa-arginine were the most effective in delivering the conjugates to the cells. The subcellular distribution of the conjugates was found to be dependent on the nature of substituents on the porphyrin macrocycle. The conjugates bearing a hydrophobic porphyrin localized preferentially in the endoplasmic reticulum and were significantly more phototoxic to HEp2 cells than the carboxylic acid functionalized porphyrin conjugates, which localized mainly in the lysosomes.
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PMID:Peptide-mediated cell transport of water soluble porphyrin conjugates. 1648 Feb 71

The UEV domain of the TSG101 protein functions in the vacuolar protein-sorting pathway and in the budding process of HIV-1 and other retroviruses by recognizing ubiquitin in proteins tagged for degradation and short sequences in viral proteins containing an essential and well conserved PTAP motif, respectively. A deep understanding of these interactions is key to the rational design of much-needed novel antivirals. Here, the crystal structure of the TSG101 UEV domain (TSG101-UEV) is presented. TSG101-UEV was crystallized in the presence of PEG 4000 and ammonium sulfate. Under these conditions, crystals were obtained in space group R3, with unit-cell parameters a = b = 97.9, c = 110.6 A, alpha = beta = 90, gamma = 120 degrees . Phases were solved by molecular replacement and the crystal structure of TSG101-UEV was refined to an R factor of 18.8% at 2.2 A resolution. A comparison between the crystal structure and previously reported NMR structures has revealed significant differences in the conformation of one of the loops implicated in ubiquitin recognition. Also, the resulting structure has provided information about the presence of water molecules at the binding interface that could be of relevance for peptide recognition.
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PMID:Structure of human TSG101 UEV domain. 1655 48

Present study aims to enhance the efficacy of liposomes as an adjuvant by steric protection and strengthen the path of vaccine research. PEG grafted liposomes carrying epitopes on their surface showed enhanced adjuvanticity than liposomes carrying epitopes for elicitation and prolongation of immune response to an antigenic epitope of gp41, a transmembrane protein of HIV-1. The multiples of epitope were incorporated onto the surface of liposomes by conjugating them with phosphatidylethanolamine that was used in the formulation of liposomes at an optimized ratio. Furthermore, the liposomes carrying epitopes on their surface were sterically protected by shielding with methoxy-poly(ethylene glycol), mass 20 kDa. Methoxy-poly(ethylene glycol) was activated to its electrophilic N-succinimide carbonate derivative, methoxy-poly(ethylene glycol)-N-succinimide carbonate, that formed a urethane linkage with the amino group of phosphatidylethanolamine. The epitope was covalently coupled to phosphatidylethanolamine through an amide bond between the -COOH group of the epitope and -NH2 group of phosphatidylethanolamine under the catalysis of 1-ethyl-3-(3-dimethylaminopropy-1)-carbodiimide. PEG grafted epitopes carrying liposomes showed about two times higher immune response and prolonged persistence of antibodies than that of liposomes carrying epitopes without PEG moieties.
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PMID:Adjuvanticity of stealth liposomes on the immunogenicity of synthetic gp41 epitope of HIV-1. 1657 86

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