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Results for “Reverse Transcriptase Inhibitors”

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PubMed1998

Lamivudine resistance of HIV type 1 does not delay development of resistance to nonnucleoside HIV type 1-specific reverse transcriptase inhibitors as compared with wild-type HIV type 1.

We compared the development of resistance toward BI-RG-587 (nevirapine) and alpha-APA R89439 (loviride) starting from the wild-type HIV-1 strain IIIB and the 3TC-resistant HIV-1 strain containing the M184V mutation. The reverse transcriptase of the M184V mutant has been reported to have a higher fidelity. Our experiments showed that there was no significant delay in virus breakthrough of the M184V mutant as compared with the wild-type virus. We therefore conclude that the reported higher fidelity of the M184V mutant does not lead to a delay in the development of resistance to the nonnucleoside reverse transcriptase inhibitors nevirapine and loviride.

Acetamides↗

PubMed1996

Genotypic and phenotypic changes during culture of a multinucleoside-resistant human immunodeficiency virus type 1 strain in the presence and absence of additional reverse transcriptase inhibitors.

The observation that human immunodeficiency virus type 1 (HIV-1) mutations conferring resistance to one reverse transcriptase (RT) inhibitor may suppress resistance to other RT inhibitors provides a rationale for treating HIV-1 with certain RT inhibitor combinations. We examined phenotypic and genotypic changes during culture of a multinucleoside (zidovudine, didanosine, zalcitibine, and stavudine)-resistant HIV-1 strain with and without additional RT inhibitors (nevirapine and lamivudine). The development of nevirapine or lamivudine resistance by the multinucleoside-resistant strain was not accompanied by a reduction in zidovudine or didanosine resistance.

Antiviral Agents↗

PubMed2006

Non-nucleoside HIV-1 reverse transcriptase inhibitors, Part 7. Synthesis, antiviral activity, and 3D-QSAR investigations of novel 6-(1-naphthoyl) HEPT analogues.

A series of novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues bearing a 6-(1-naphthoyl) group of non-nucleoside human immunodeficiency virus (HIV) reverse transcriptase inhibitors were synthesized and evaluated for their activity against HIV-1 and HIV-2. It was found that most of these compounds showed good activity against HIV-1. Among them, compound 5-isopropyl-6-(1-naphthoyl)-1-[(2E)-3-phenylallyl]-2,4-pyrimidinedione (23) displayed the greatest inhibitory potency (IC(50)=0.14 muM), which is about 35-fold more active than HEPT and DDI. To rationalize the relationships between structure and activity of these novel compounds, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was also generated. The results provided a tool for guiding the further design of more potent antiviral agents and for predicting the affinity of related compounds.

Anti-HIV Agents↗

PubMed2005

Pre-incubation of cell-free HIV-1 group M isolates with non-nucleoside reverse transcriptase inhibitors blocks subsequent viral replication in co-cultures of dendritic cells and T cells.

In order to study the inhibitory effect of various reverse transcriptase inhibitors (RTIs) on cell-free HIV, we adapted a recently described in vitro system, based on co-cultures of dendritic cells and resting CD4 T cells, modelling early target cells during sexual transmission. The compounds tested included the second-generation non-nucleoside RTI (NNRTI) TMC-120 (R147681, dapivirine) and TMC-125 (R165335, travertine), as well as the reference nucleoside RTI AZT (zidovudine), the nucleotide RTI PMPA (tenofovir) and the NNRTI UC-781. The virus strains included the reference strain HIV-1Ba-L and six primary isolates, representative of the HIV-1 group M pandemic. They all display the non-syncytium-inducing and CCR5 receptor-using (NSI/R5) phenotype, important in transmission. Cell-free virus was immobilized on a poly-L-lysine (PLL)-treated microwell plate and incubated with compound for 1 h. Afterwards, the compound was thoroughly washed away; target cells were added and cultured for 2 weeks, followed by an extended culture with highly susceptible mitogen-activated T cells. Viral production in the cultures was measured on supernatant with HIV antigen ELISA. Negative results were confirmed by showing absence of proviral DNA in the cells. TMC-120 and TMC-125 inhibited replication of HIV-1Ba-L with average EC50 values of 38 nM and 117 nM, respectively, whereas the EC50 of UC-781 was 517 nM. Complete suppression of virus and provirus was observed at compound concentrations of 100, 300 and 1000 nM, respectively. Inhibition of all primary isolates followed the same pattern as HIV-1Ba-L. In contrast, pre-treating the virus with the nucleotide RTI PMPA and AZT failed to inhibit infection even at a concentration of 100000 nM. These data clearly suggest that NNRTIs inactivate RT enzymatic activity of different viral clades (predominant in the epidemic) and might be proposed for further testing as a sterilizing microbicide worldwide.

CD4-Positive T-Lymphocytes↗

PubMedDate not supplied

In vitro metabolism of L-696,229, an HIV-1 reverse transcriptase inhibitor in rats and humans. Hepatic and extrahepatic metabolism and identification of enzymes involved in the hepatic metabolism.

The metabolism of L-696,229, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-o ne, a potent human immunodeficiency virus-type 1 reverse transcriptase inhibitor, by rat liver, lung, gut, and kidney microsomes has been studied. L-696,229 was metabolized by rat liver microsomes to several products: the 5 alpha-hydroxyethyl (M1); 5,6-dihydrodiol (M2); 6'-hydroxy (M3); 6-hydroxymethyl (M4); and 5-vinyl (M5) metabolites. For these pathways, liver was the most active metabolizing organ, whereas lung was the major extrahepatic organ in the drug metabolism. In all tissues tested, M1 was the major metabolite. With the exception of M3, gender differences in the hepatic formation of all metabolites were observed. Enzymes responsible for the hepatic metabolism of L-696,229 in rats were also investigated using various enzyme inducers and polyclonal antibodies to rat P-450. Treatment of male rats with dexamethasone (DX) or phenobarbital (PB) caused significant increases in the hepatic formation of the gender-dependent metabolites. Methylcholanthrene (3-MC) greatly enhanced the hepatic formation of M1, M3, and M4. Immunoinhibition studies suggested that CYP2B1/2 and 2E1 were not involved in L-696,229 metabolism, whereas CYP1A was partly responsible for the formation of M1 in untreated rats. CYP3A played an important role in the formation of M1, M2, M4, and M5 in untreated and DX-treated rats. In PB-treated rats, CYP2B1/2 was involved in the increased formation of M1 and M4, whereas CYP3A was partly involved in the enhanced M2 and M4 formation, and primarily responsible for the increased M5 formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed2000

Therapy with efavirenz plus indinavir in patients with extensive prior nucleoside reverse-transcriptase inhibitor experience: a randomized, double-blind, placebo-controlled trial.

A randomized, double-blind, placebo-controlled trial compared efavirenz (600 mg every 24 h) plus indinavir (1000 mg every 8 h) with placebo (every 24 h) plus indinavir (800 mg every 8 h) among 327 nucleoside analogue reverse-transcriptase inhibitor (NRTI)-experienced human immunodeficiency virus (HIV)-infected adults. Patients received </=2 concomitant NRTIs. Eligible patients had CD4 cell counts >50 cells/mm(3), >10,000 plasma HIV-1 RNA copies/mL, and no prior protease inhibitor or non-NRTI therapy. Patients had a mean of 2.8 years of prior NRTI therapy. At 24 weeks, plasma HIV-1 RNA level was <400 copies/mL in 68.2% of efavirenz versus 52.4% of placebo recipients (P=.004). CD4 cell count increases were 104+/-9 cells/mm(3) and 77+/-10 cells/mm(3) in efavirenz and placebo recipients, respectively (P=.023). Responses in efavirenz recipients were sustained at 48 weeks. Thus, efavirenz plus indinavir with concomitant NRTIs is effective therapy for NRTI-experienced patients.

Adult↗

PubMed2004

Induction of cellular resistance to nucleoside reverse transcriptase inhibitors by the wild-type breast cancer resistance protein.

Breast cancer resistance protein (BCRP/ABCG2) is a novel member of ATP-binding cassette transporters, which induce multidrug resistance in cancer cells. We previously reported that a high level of BCRP expression in CD4(+) T cells conferred cellular resistance to nucleoside reverse transcriptase inhibitors (NRTIs) of human immunodeficiency virus type 1 (HIV-1). However, this BCRP was found to have a mutation of Arg to Met at position 482 (BCRP(R482M)). The present study demonstrated that the wild-type BCRP (BCRP(WT)) also conferred cellular resistance to NRTIs. MT-4 cells (a CD4(+) T-cell line) highly expressing BCRP(WT) (MT-4/BCRP) were generated and the expression of BCRP(WT) was confirmed by genotypic and phenotypic analyses. Compared to the parental MT-4 cells, MT-4/BCRP cells displayed resistance to zidovudine (AZT) in terms of antiviral activity as well as drug cytotoxicity. In addition, other NRTIs were also less inhibitory to HIV-1 replication in MT-4/BCRP cells than in MT-4 cells. Significant reduction of intracellular AZT accumulation was observed in MT-4/BCRP cells. An analysis for intracellular metabolism of AZT suggested that the resistance was attributed to the increased efflux of AZT and its metabolites in MT-4/BCRP cells. Furthermore, the BCRP-specific inhibitor fumitremorgin C completely restored the reduction of AZT in MT-4/BCRP cells. These results indicate that, like BCRP(R482M), BCRP(WT) also plays an important role in cellular resistance to NRTIs.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2001

Simultaneous quantitation of nucleoside HIV-1 reverse transcriptase inhibitors by short-end injection capillary electrochromatography on a beta-cyclodextrin-bonded silica stationary phase.

As part of our on-going study of the analysis and quantitation of anti-HIV nucleosides, a capillary electrochromatography (CEC) method has been developed for the simultaneous quantitation of nucleoside HIV reverse transcriptase inhibitors (NRTIs), i.e. zidovudine (AZT), lamivudine (3TC), didanosine (ddA) and its administrated form (ddI), stavudine (d4T) and hivid (ddC). CEC on chiral stationary phase has mainly been dedicated to the separation of enantiomers. However, this paper explores an original application of a beta-cyclodextrin-bonded silica packed column, taking advantage of the internal hydrophobicity of the polysaccharide to separate the NRTIs. The influence of several parameters (pH buffer, ionic strength, acetonitrile content, temperature and voltage) has been investigated using the short-end injection technique to achieve baseline separation in a short-time analysis before quantitation.

Chromatography, Micellar Electrokinetic Capillary↗

PubMed1999

Susceptibility of lamivudine-resistant hepatitis B virus to other reverse transcriptase inhibitors.

The emergence of resistant hepatitis B virus (HBV), with mutations in the YMDD motif of the polymerase gene after treatment with lamivudine, is becoming an important clinical problem. In this study, susceptibility of wild-type and lamivudine-resistant HBV M552I, M552V, and L528M/M552V mutants to other reverse transcriptase inhibitors was investigated by transient transfection of full-length HBV DNA into human hepatoma cells. HBV DNA replication was monitored by Southern blot hybridization, which showed the presence of a single-stranded band (representative of the HBV replicative intermediates) in the drug-free, wild-type HBV-transfected cells. This band was diminished in the samples of wild-type HBV DNA treated with either lamivudine, adefovir, or lobucavir. The band intensities from the lamivudine-resistant mutants were not decreased by treatment with lamivudine, but were decreased by the treatments with adefovir or lobucavir. In contrast, penciclovir and nevirapine did not diminish the intensity of the single-stranded band of wild-type HBV or the lamivudine-resistant mutants. These results demonstrate that lamivudine-resistant HBV is susceptible to adefovir and lobucavir. Lamivudine-resistant HBV should be treated with adefovir or lobucavir, and combination therapy with lamivudine and adefovir/lobucavir may prevent the emergence of lamivudine-resistant HBV.

Acyclovir↗

PubMed2002

Tenofovir exhibits low cytotoxicity in various human cell types: comparison with other nucleoside reverse transcriptase inhibitors.

Clinical studies with tenofovir disoproxil fumarate, an oral prodrug of the nucleotide analog tenofovir, recently approved for the treatment of HIV, have demonstrated antiviral activity and good tolerability in HIV-infected patients. In order to better understand the cytotoxicity profile of tenofovir relative to the other nucleoside reverse transcriptase inhibitors (NRTIs), the in vitro effects of these agents were evaluated in various human cell types. Tenofovir inhibited the proliferation of liver-derived HepG2 cells and normal skeletal muscle cells with CC(50) values of 398 and 870 microM, respectively. In comparison, ZDV, ddC, ddI, d4T, and abacavir all showed lower CC(50) values in these two cell types. Evaluation of hematopoietic toxicity revealed that tenofovir was less cytotoxic towards erythroid progenitor cells (CC(50)>200 microM) than ZDV, d4T, and ddC (CC(50)=0.06-5 microM). Despite some degree of donor-to-donor variability, the inhibitory activity of the tested NRTIs against myeloid cell lineage, in the order of decreasing severity, was consistently ddC>ZDV>d4T>tenofovir>3TC. Finally, tenofovir showed substantially weaker effects on proliferation and viability of renal proximal tubule epithelial cells than cidofovir, a related nucleotide analog with the potential to induce renal tubular dysfunction. In conclusion, tenofovir exhibited weak cytotoxic effects in all cell types tested with less in vitro cytotoxicity than the majority of NRTIs currently used for the treatment of HIV disease.

Adenine↗

PubMedDate not supplied

Comparative CD4 T-cell responses of reverse transcriptase inhibitor therapy with or without nelfinavir matched for viral exposure.

BACKGROUND: Therapy of HIV infection with protease inhibitors (PIs) may be associated with improvements in CD4 T-cell number via a mechanism that is independent of effects on plasma viral load (VL). PURPOSE: To compare CD4 responses of patients who receive reverse transcriptase inhibitor (RTI) therapies with or without a PI, matched for viral exposure. METHODS: Patient data were analyzed from two prospective randomized trials of antiviral therapy with or without nelfinavir. Total viral exposure over 24 weeks was estimated by viral area under the curve (AUC), which reflects baseline viral load, slope of virologic decay, viral nadir, and duration of suppression. Patients were stratified into quartiles on the basis of viral AUC, and CD4 T-cell responses were evaluated between PI-containing and RTI-only treatment groups within each quartile. RESULTS: In both trials, patients receiving nelfinavir had greater CD4 T-cell increases than patients receiving RTI alone. Analysis of variance modeling revealed increased CD4 T-cell responses in PI-treated groups at all time points after the second week. These differences were significant (p <.05) at weeks 12, 24, 28, 32, 36, 40, and 48 in one study, and weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, and 44 in the other. Within quartiles matched for viral AUC, absolute CD4 T-cell change from baseline was greater in the PI-treated patients at 84% (101/120) of time points analyzed. CONCLUSION: Nelfinavir-containing therapy is associated with enhanced increases in CD4 T-cell number compared to RTI therapy alone with equivalent antiviral effect. These data suggest that PIs influence CD4 T-cell number through a nonvirologic effect.

Anti-HIV Agents↗

PubMed1995

Species differences in the metabolism of a potent HIV-1 reverse transcriptase inhibitor L-738,372. In vivo and in vitro studies in rats, dogs, monkeys, and human.

In vivo and in vitro metabolism of 6-chloro-4(S)-cyclopropyl-3,4-dihydro-4-((2-pyridyl) ethynyl)quinazolin-2(1H)-one (L-738,372), a potent human immunodeficiency virus-type 1 reverse transcriptase inhibitor, has been investigated in rats, dogs, and monkeys. Following 0.9 mg/kg iv and 9 mg/kg po doses, systemic blood clearance (CLB) and bioavailability (F) of L-738,372 were species-dependent and inversely related (CLB = 48, 15, and 3 ml/min/kg; F = 6, 62 and 94%, in dogs, rats, and monkeys, respectively). Incubation of L-738,372 with rat liver slices and liver microsomes from all species studied led to the formation of two hydroxylated metabolites, M1 and M2. Kinetic studies of the microsomal metabolism of L-738,372 indicated that M1 was formed by a much higher affinity, but lower capacity enzyme(s) than that which catalyzed M2 formation in rats, dogs, and monkeys. The total intrinsic clearance of metabolite formation (CL(int) total = CL(int) M1 + CL(int) M2) was highest in dogs, followed by rats and monkeys. In dogs, CL(int) total was caused almost exclusively by CL(int) M1. Extrapolation of the CL(int) total values to the hepatic clearances (19, 8.4, and 0.9ml/min/kg in dogs, rats, and monkeys, respectively) showed a similar rank order to the CLB observed in vivo. Good agreement between these in vivo and in vitro results suggests that the species differences in hepatic first-pass metabolism, and not the intrinsic absorption, contributed significantly to the observed differences in F.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2004

Design, synthesis and biological evaluation of novel non-nucleoside HIV-1 reverse transcriptase inhibitors with broad-spectrum chemotherapeutic properties.

Acquired immunodeficiency syndrome (AIDS) results from infection by the retrovirus, human immunodeficiency virus (HIV). HIV is the most significant risk factor for many opportunistic infections like tuberculosis, hepatitis, bacterial infections, etc. In this paper, we designed aminopyrimidinimino isatin lead compound as a novel non-nucleoside reverse transcriptase inhibitor with broad-spectrum chemotherapeutic properties for the effective treatment of AIDS and AIDS-related opportunistic infections. Compound 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7[[N(4)-[3'-(4'-amino-5'-trimethoxybenzylpyrimidin-2'-yl)imino-1'-(5-fluoroisatinyl)]methyl]-N(1)-piperazinyl]-3-quinoline carboxylic acid (12) emerged as the most potent broad-spectrum chemotherapeutic agent active against HIV, HCV, Mycobacterium tuberculosis and various pathogenic bacteria.

Animals↗

PubMed2006

Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor.

Despite the progress of the past two decades, there is still considerable need for safe, efficacious drugs that target human immunodeficiency virus (HIV). This is particularly true for the growing number of patients infected with virus resistant to currently approved HIV drugs. Our high throughput screening effort identified a benzophenone template as a potential nonnucleoside reverse transcriptase inhibitor (NNRTI). This manuscript describes our extensive exploration of the benzophenone structure-activity relationships, which culminated in the identification of several compounds with very potent inhibition of both wild type and clinically relevant NNRTI-resistant mutant strains of HIV. These potent inhibitors include 70h (GW678248), which has in vitro antiviral assay IC(50) values of 0.5 nM against wild-type HIV, 1 nM against the K103N mutant associated with clinical resistance to efavirenz, and 0.7 nM against the Y181C mutant associated with clinical resistance to nevirapine. Compound 70h has also demonstrated relatively low clearance in intravenous pharmacokinetic studies in three species, and it is the active component of a drug candidate which has progressed to phase 2 clinical studies.

Alkynes↗

PubMed2006

Nucleoside reverse transcriptase inhibitors prevent HIV protease inhibitor-induced atherosclerosis by ubiquitination and degradation of protein kinase C.

HIV protease inhibitors are important pharmacological agents used in the treatment of HIV-infected patients. One of the major disadvantages of HIV protease inhibitors is that they increase several cardiovascular risk factors, including the expression of CD36 in macrophages. The expression of CD36 in macrophages promotes the accumulation of cholesterol, the development of foam cells, and ultimately atherosclerosis. Recent studies have suggested that alpha-tocopherol can prevent HIV protease inhibitor-induced increases in macrophage CD36 levels. Because of the potential clinical utility of using alpha-tocopherol to limit some of the side effects of HIV protease inhibitors, we tested the ability of alpha-tocopherol to prevent ritonavir, a common HIV protease inhibitor, from inducing atherosclerosis in the LDL receptor (LDLR) null mouse model. Surprisingly, alpha-tocopherol did not prevent ritonavir-induced atherosclerosis. However, cotreatment with the nucleoside reverse transcriptase inhibitors (NRTIs), didanosine or D4T, did prevent ritonavir-induced atherosclerosis. Using macrophages isolated from LDLR null mice, we demonstrated that the NRTIs prevented the upregulation of CD36 and cholesterol accumulation in macrophages. Treatment of LDLR null mice with NRTIs promoted the ubiquitination and downregulation of protein kinase Calpha (PKC). Previous studies demonstrated that HIV protease inhibitor activation of PKC was necessary for the upregulation of CD36. Importantly, the in vivo inhibition of PKC with chelerythrine prevented ritonavir-induced upregulation of CD36, accumulation of cholesterol, and the formation of atherosclerotic lesions. These novel mechanistic studies suggest that NRTIs may provide protection from one of the negative side effects associated with HIV protease inhibitors, namely the increase in CD36 levels and subsequent cholesterol accumulation and atherogenesis.

Animals↗

PubMed2003

Long-term complications of nucleoside reverse transcriptase inhibitor therapy.

HAART has resulted in dramatic declines in morbidity and mortality among patients infected with HIV. Increased experience with HAART has led to the detection of drug related toxicities that may compromise adherence and necessitate discontinuation of treatment and alteration of otherwise effective regimens. This article considers the major long-term complications associated with nucleoside reverse transcriptase inhibitor (NRTI) use--hyperlactatemia and lactic acidosis/hepatic steatosis, other hepatotoxicities, pancreatitis, lipodystrophy, lipoatrophy, neuropathy, and hematologic toxicities. Mechanisms by which NRTIs may produce these effects are discussed, as are differential effects of agents in this class and management options.

Acidosis, Lactic↗

PubMed2003

Nonnucleoside HIV-1 reverse transcriptase inhibitors: Part I. Synthesis and structure-activity relationship of 1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils as HEPT analogues.

1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils, which are novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues, were synthesized for evaluation as selective and potent nonnucleoside human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitors. The anti-HIV-1 activity of these compounds was assayed in vitro using HIV-1 infected MT-4 and CEM bioassays. The EC50, CC50 and SI were recorded and calculated. The appropriate position, especially in the 1-position of the naphthyl ring, led to dramatic increases in potency, in both MT-4 and CEM cellular assays. The most important compounds in this series, 1-ethoxymethyl-5-isopropyl-6-(1-naphthylmethyl)thymine 8l (IC50=17 nM, CC50=38332 nM, SI=2229) and 1-benzyloxymethyl-5-ethyl-6-(1-naphthylmethyl)thymine 8n (IC50=17 nM, CC50=32560 nM, SI=1889) were significantly more potent than HEPT (EC50=7.0 microM, CD50=740 microM) in the anti-HIV-1 in vitro cellular assay.

Cell Line↗

PubMed2001

Non-nucleoside reverse transcriptase inhibitor failure impairs HIV-RNA responses to efavirenz-containing salvage antiretroviral therapy.

In a retrospective cohort study of salvage antiretroviral combination therapy including efavirenz, 60% of 51 patients were able to suppress HIV RNA by at least 1 log10 or to less than 50 copies/ml. A lack of the previous use of non-nucleoside reverse transcriptase inhibitors was the only factor predictive of response on multivariate analysis. No patient with a viral isolate with an increased IC50 to efavirenz by virtual phenotype had a virological response

Adult↗