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 L enantiomer of 2',3'-dideoxycytidine (DDC) was recently shown to inhibit selectively human immunodeficiency virus type 1 (HIV-1) in vitro. In the current study, the potent anti-HIV activity of L-DDC was confirmed and extended to several HIV-1 and HIV-2 strains in various cell culture systems, including primary human lymphocytes and macrophages. Furthermore, its 5-fluoro congener, beta-L-2',3'-dideoxy-5-fluorocytidine (L-FDDC), was found to have more potent anti-HIV activity and a higher therapeutic index in acutely infected human peripheral blood mononuclear cells. These compounds had no marked activity against HIV-1 isolates resistant to the oxathiolane pyrimidine nucleosides (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine, but 3'-azido-3'-deoxythymidine (AZT)-resistant viruses were susceptible to L-DDC and L-FDDC. Cytotoxicity studies with human myeloid progenitor cells indicated that L-DDC and L-FDDC had median inhibitory concentrations comparable to those of AZT, DDC, and FDDC, but L-DDC and L-FDDC were significantly less toxic than AZT, DDC, and FDDC when erythroid progenitor cells were used. L-FDDC had the highest selectivity indices (6,000 and 9,000 for erythroid and myeloid progenitor cells, respectively) of all the compounds evaluated. Further preclinical development of L-FDDC is warranted in order to determine its potential usefulness in the treatment of HIV infections.
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PMID:Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro. 809 27

Variants of feline immunodeficiency virus (FIV) that possess a unique methionine-to-threonine mutation within the YMDD motif of reverse transcriptase (RT) were selected by culturing virus in the presence of inhibitory concentrations of (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC]. The mutants were resistant to (-)-FTC and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) and additionally exhibited low-level resistance to 2',3'-dideoxycytidine (ddC). DNA sequence analysis of the RT-encoding region of the pol gene amplified from resistant viruses consistently identified a Met-to-Thr mutation in the YMDD motif. Purified RT from the mutants was also resistant to the 5'-triphosphate forms of 3TC, (-)-FTC, and ddC. Site-directed mutants of FIV were engineered which contain either the novel Met-to-Thr mutation or the Met-to-Val mutation seen in oxathiolane nucleoside-resistant HIV-1. Both site-directed mutants displayed resistance to 3TC, thus confirming the role of these mutations in the resistance of FIV to beta-L-3'-thianucleosides.
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PMID:A novel Met-to-Thr mutation in the YMDD motif of reverse transcriptase from feline immunodeficiency virus confers resistance to oxathiolane nucleosides. 903 72

Following the recent discoveries that some L-nucleosides are more or equal potent than their D-counterparts, we synthesized 2'-deoxy-2',2'-difluoro-L-erythro-pentofuranosyl nucleosides as potential antiviral agents. The target compounds were synthesized via the key intermediates 7a or 7b from L-gulono gamma-lactone. Compound 2 was oxidatively cleaved and coupled with ethyl bromodifluoroacetate in the presence of activated zinc under Reformatsky conditions to obtain a diasteomeric mixture of 4(R) and 4(S), in a 4:1 ratio. The major 4(R) isomer was cyclized and treated appropriately to obtain the mesylate 8a or 8b, which was condensed with various silyl-protected pyrimidines. Condensation of the alcohol 7a or 7b with 6-chloropurine under Mitsunobu conditions afforded the 6-chlorpurine analogs 53a or 53b and 54a or 54b. Further treatment of the compounds 53a, 54a and 53b, 54b afforded the inosine and adenine derivatives 57-60, respectively. The condensation of 2-amino-6-chloropurine with compound 8a and subsequent treatment with 2-mercaptoethanol/sodium methoxide afforded the guanine analogs 63 and 64. All of the synthesized nucleosides 31-52, 57-60, 63, and 64 were evaluated for antiviral activity and for cellular toxicity. Adenine derivative 57 showed a moderate activity against HIV-1 in PBM cells (3.4 microM). None of the other compounds showed any significant activities against HIV-1, HBV, HSV-1, HSV-2, and toxicity in Vero, CEM, and PBM cell lines up to 100 microM. The X-ray structure of the 5-iodocytosine analog showed a 2'-exo/3'-endo conformation for the carbohydrate moiety, which is different from those of the biologically active compounds (-)-FTC and L-FMAU.
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PMID:Structure-activity relationships of 2'-deoxy-2',2'-difluoro-L-erythro-pentofuranosyl nucleosides. 935 30

Treatment of wild-type human immunodeficiency virus [HIV-1(IIIB)]-infected cell cultures with the thiocarboxanilide UC-781 under low selective pressure (i.e., 0.01 microg/ml) resulted in the emergence of V106A RT mutant virus. On increasing drug concentrations (stepwise up to 30 microg/ml) the virus retained the V106A RT mutation but acquired the novel F227L mutation in the RT genome in addition to the L100I, K1O1I, and Y181C mutations. This multiple-mutant virus proved highly resistant to virtually all nonnucleoside RT inhibitors (NNRTIs) (e.g., nevirapine, delavirdine, and loviride), but retained full sensitivity to nucleoside analogs such as AZT, ddI, (-)FTC, and 3TC. The F227 amino acid is highly conserved in HIV-1 strains and forms part of the NNRTI-binding pocket. Our model suggests a hydrophobic interaction between F227 and the chloro atom of UC-781.
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PMID:A novel mutation (F227L) arises in the reverse transcriptase of human immunodeficiency virus type 1 on dose-escalating treatment of HIV type 1-infected cell cultures with the nonnucleoside reverse transcriptase inhibitor thiocarboxanilide UC-781. 949 16

Primarily resulting as a spin-off of the search for effective anti-HSV or anti-HIV agents, several compounds have been identified as effective and promising candidate anti-HBV drugs, i.e. famciclovir (penciclovir), BMS-200475, lamivudine (3TC), (-)FTC, L(-)Fd4C, L-FMAU, DAPD (DXG), bis(POM)-PMEA and bis(POC)-PMPA. They all inhibit HBV replication in Hep G2 2.2.15 at concentrations that are well below the cytotoxicity threshold. All these nucleoside analogues require three phosphorylation steps to be active, in their triphosphate form, as inhibitors of the HBV DNA polymerase, except for PMEA (adefovir) and PMPA (tenofovir), which need only two phosphorylation steps, to PMEApp and PMPApp, respectively, to interact as chain terminators with the HBV DNA polymerase reaction. Several of these compounds (for example, famciclovir, lamivudine and adefovir) have proven to be efficacious in the duck and/or woodchuck hepatitis models, and, accordingly, famciclovir, lamivudine and adefovir have also proven to be effective (i.e. in reducing HBV DNA levels) in patients with chronic HBV infection. Yet, famciclovir and lamivudine may lead to the emergence of resistance mutations (i.e. L528M and M552V/I) in the HBV DNA polymerase upon long-term treatment. These penciclovir- and lamivudine-resistant HBV mutants still retain susceptibility to adefovir, which, in turn, has so far not been found to engender resistance mutations in HBV. As has become obvious from the experience with the treatment of HIV infections, future HBV chemotherapy may reside in combination drug therapy so as to achieve the highest possible virus reduction, thereby minimizing the likelihood of drug resistance development.
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PMID:Perspectives for the treatment of hepatitis B virus infections. 1041 52

Of all of the nucleoside inhibitors approved by the FDA for treatment of AIDS, (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) is the only one with the unnatural (-)-beta-L configuration. The fluorinated derivative (-)-beta-2', 3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and its triphosphate form have also been reported to have excellent antiretroviral activity against HIV-1 reverse transcriptase (RT). Preliminary results of clinical trials suggest that (-)-FTC is 6- to 10-fold more potent than 3TC. However, the molecular mechanism for the observed enhanced clinical potency of (-)-FTC to inhibit viral replication is not understood. The present mechanistic studies used a transient kinetic approach and were designed to compare the incorporation of 3TC-TP and (-)-FTC-TP into DNA by HIV-1 RT and illuminate key features that may play a role in the differential potency. Here we show that (-)-FTC-TP is incorporated 10-fold more efficiently than 3TC-TP during HIV-1 RT-catalyzed RNA-dependent DNA synthesis. The enhanced incorporation efficiency of (-)-FTC-TP may be a key mechanistic feature that, in part, is responsible for the enhanced potency of (-)-FTC observed in ongoing clinical trials.
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PMID:Mechanistic studies show that (-)-FTC-TP is a better inhibitor of HIV-1 reverse transcriptase than 3TC-TP. 1046 41

The statement made by Health Minister Mantho Tshabalala-Msimang on the cause of the death of trial participants evoked a contradictory response from the South Africa's Medicines Control Council (MCC). In his speech, the minister attributed the cause of these deaths to nevirapine, whose trial has been suspended but the study still continues. Opposition parties have accused the minister of trying to demonize nevirapine as justification for not providing free antiretroviral treatment to pregnant women with HIV. The trial in question, FTC-302, is a combination therapy in the long-term treatment of adult HIV infection. The trial compares Triangle's emtricitabine with lamivudine when combined with stavudine and nevirapine. Two days after the statement was made public, MCC responded that evidence is still inconclusive while, at the same time, points the cause of these deaths to drug interaction. Furthermore, Tshabalala-Msimang's comments irritated AIDS activists, who had already expressed outrage at the exclusion of top AIDS researchers from the controversial panel of experts being set up to advice President Thabo Mbeki on AIDS. Despite the controversy, AIDS activists had some cause to celebrate when Pfizer announced the donation of free fluconazole that is used to prevent relapse of cryptococcal meningitis.
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PMID:South Africa's Medicines Control Council contradicts Health Minister. 1090 48

Treating HIV infections with drugs that block viral replication selects for drug-resistant strains of the virus. Particular inhibitors select characteristic resistance mutations. In the case of the nucleoside analogs 3TC and FTC, resistant viruses are selected with mutations at amino acid residue 184 of reverse transcriptase (RT). The initial change is usually to M184I; this virus is rapidly replaced by a variant carrying the mutation M184V. 3TC and FTC are taken up by cells and converted into 3TCTP and FTCTP. The triphosphate forms of these nucleoside analogs are incorporated into DNA by HIV-1 RT and act as chain terminators. Both of the mutations, M184I and M184V, provide very high levels of resistance in vivo; purified HIV-1 RT carrying M184V and M184I also shows resistance to 3TCTP and FTCTP in in vitro polymerase assays. Amino acid M184 is part of the dNTP binding site of HIV-1 RT. Structural studies suggest that the mechanism of resistance of HIV-1 RTs carrying the M184V or M184I mutation involves steric hindrance, which could either completely block the binding of 3TCTP and FTCTP or allow binding of these nucleoside triphosphate molecules but only in a configuration that would prevent incorporation. The available kinetic data are ambiguous: one group has reported that the primary effect of the mutations is at the level of 3TCTP binding; another, at the level of incorporation. We have approached this problem using assays that monitor the ability of HIV-1 RT to undergo a conformational change upon binding a dNTP. These studies show that both wild-type RT and the drug-resistant variants can bind 3TCTP at the polymerase active site; however, the binding to M184V and M184I is somewhat weaker and is sensitive to salt. We propose that the drug-resistant variants bind 3TCTP in a strained configuration that is salt-sensitive and is not catalytically competent.
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PMID:The role of steric hindrance in 3TC resistance of human immunodeficiency virus type-1 reverse transcriptase. 1087 73

A series of unnatural L-nucleosides such as 3TC, FTC and L-FMAU have been found to be potent antiviral agents. The mode of action of L-nucleosides has been found to be similar to that of D-nucleosides as antiviral agents, despite their unnatural stereochemistry, that is, nucleotide formation by kinases followed by interaction with the reverse transcriptase (RT) of HIV or DNA polymerase. To date, the mode of action of nucleoside inhibitors at the molecular level with respect to the active conformations of the 5'-triphosphates as well as the interaction with the RT is not known. Recently, the X-ray crystal structure of the RT-DNA-dTTP catalytic complex has been reported. Computer modeling has been performed for several pairs of D- and L-nucleoside inhibitors using the HIV-1 RT model and crystal coordinate data from a subset of the protein surrounding the deoxynucleoside triphosphate (dNTP) binding pocket region. Results from our modeling studies of D-/L-zidovudine, D-/L-3TC, D-/L-dideoxycytosine triphosphates, dTTP and dCTP show that their binding energies correlate with the reported 50% effective concentrations. Modeling results are also discussed with respect to favorable conformations of each inhibitor at the dNTP site in the polymerization process. Additionally, the clinically important M184V mutation, which confers resistance against 3TC and FTC, was studied with our modeling system. The binding energy patterns of nucleoside inhibitors at the M184V mutation site correlate with the reported antiviral data.
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PMID:Molecular modeling approach to understanding the mode of action of L-nucleosides as antiviral agents. 1112 Sep 56

Reports at the 5th Conference on Retroviruses and Opportunistic Infections addressed new anti-HIV agents in primary phases of development that offer treatment alternatives to people with little or no treatment history and individuals with few treatment choices. FTC, a new nucleoside analog produced by Triangle Pharmaceuticals, is an alternative to 3TC. F-ddA (lodenosine), a nucleoside analog licensed by US Bioscience, is structurally similar to ddI and is reported to have good bioavailability, once-a-day dosing, and no bone marrow suppression. F-ddA has also shown in vitro activity against multidrug-resistant strains of HIV. Adult and pediatric studies are currently being conducted by the National Cancer Institute (NCI) and US Bioscience. Oral versus IV PMPA shows promising results as a possible alternative for 3TC- and AZT-experienced patients. Further testing is being done by Gilead Sciences and HIV Network for Prevention Trials (HIVNET). Abbott Laboratories is developing a second-generation protease inhibitor, ABT-378, which has a ten-fold greater antiviral activity in vitro than the original, ritonavir. It is administered with ritonavir to increase ABT-378 levels in the blood, but has no food requirements, and less severe side effects. Two trials are being conducted: one for patients who are treatment-naive and the second for patients who are failing other protease inhibitors. Immune-based therapies, such as Leukine (GM-CSF), are used to handle neutropenia and offset bone marrow toxicities from drugs. Concerns that GM-CSF may increase viral replication may be balanced by using highly active antiretroviral therapy. FP-21399, developed by Lexigen Pharmaceuticals, is being tested as an HIV fusion inhibitor.
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PMID:Looking down the drug pipeline. 1136 93


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