Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resistance of HIV-1 reverse transcriptase (RT) to nucleoside analogs (e.g. AZT, ddC and 3TC) is conferred by various amino acid substitutions or combinations thereof on the RT molecule. The M184V mutation, that confers high and low-level resistance to 3TC and ddC, respectively, can restore sensitivity to AZT when introduced into RT against a background of AZT-resistance. The K65R mutation, that confers low level resistance to both 3TC and ddC, can also restore sensitivity to AZT. This information is of potential utility in choosing combinations of anti-viral drugs for clinical use. To explore this subject further, we have used an endogenous RT reaction to study mutated viruses containing M184V alone or M184V combined with each of the K65R, E89G or both the M41L and T215Y substitutions. Endogenous assays possess the advantage of utilizing genomic RNA as template in a reaction mixture that includes each of tRNALys.3 and viral nucleocapsid protein, necessary for specific initiation of reverse transcription, as well as all other viral proteins that might impact on this process. We now show that viruses containing both M184V and K65R displayed synergistic resistance to 3TC triphosphate (3TCTP), while the same combination yielded the same level of resistance to ddC triphosphate (ddCTP) as that manifested by K65R alone. The combination of M184V and E89G displayed synergistic resistance against ddCTP but not 3TCTP, while viruses containing only E89G were highly resistant to 3TCTP and displayed low-level resistance to ddCTP. The results show that endogenous RT assays can reveal variable synergistic, antagonistic, or neutral effects in regard to drug sensitivity, depending on the presence of specific amino acid substitutions in RT itself.
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PMID:Endogenous reverse transcriptase assays reveal synergy between combinations of the M184V and other drug resistance-conferring mutations in interactions with nucleoside analog triphosphates. 951 45

An azidothymidine (AZT)-resistant virus strain (HIV-1/AZT) (containing the 67 Asp --> Asn, 70 Lys --> Arg, 215 Thr --> Phe and 219 Lys --> Gln mutations into its reverse transcriptase) was grown in the combined presence of 2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) and the nonnucleoside reverse transcriptase inhibitor (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-dih ydroquinoxaine-2(1H)-thione (quinoxaline HBY 097). Replication of HIV-1/AZT was inhibited to a significantly greater extent by the combination of 3TC and quinoxaline HBY 097 than by either drug alone. Virus breakthrough was markedly delayed in the combined presence of 3TC and HBY 097 at drug concentrations as low as 0.05 microg/mL and 0.0025 microg/mL, respectively. The virus that was recovered after exposure to the compounds (3TC and HBY 097) individually had acquired, in the genetic AZT-resistance background of HIV-1/AZT, 103 Lys --> Glu and 106 Val --> Ala mutations. The 103 Lys --> Glu mutation had not been observed before. However, both virus mutants retained marked sensitivity to HBY 097. In all cases, the genotypic AZT-resistance mutations were maintained in the mutant virus RT genomes, and the viruses also remained phenotypically resistant to AZT. Given the exquisite potency of a concomitant combination of 3TC and HBY 097 in suppressing virus replication, this drug combination should be further pursued in clinical trials in HIV-1-infected individuals.
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PMID:Retention of marked sensitivity to (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-di hydroquin oxaline-2(1H)-thione (HBY 097) by an azidothymidine (AZT)-resistant human immunodeficiency virus type 1 (HIV-1) strain subcultured in the combined presence of quinoxaline HBY 097 and 2',3'-dideoxy-3'-thiacytidine (lamivudine). 951 72

Recent clinical trials examining 3'-azido-3'-deoxythymidine (AZT, zidovudine, or Retrovir) combined with L-2', 3'-dideoxy-3'-thiacytidine (3TC or lamivudine) have shown that combination therapy with these nucleoside analogs affords significant virological and clinical benefits. The addition of 3TC to AZT delays AZT resistance in therapy-naive patients and can restore viral AZT susceptibility in patients who previously received AZT alone. In some AZT-experienced patients, the virological response to AZT-3TC therapy is not sustained and virus resistant to both drugs can be identified. To gain insight into the possible mechanism of dual resistance, we studied a recently described variant resistant to both AZT and 3TC and obtained by simultaneous passage of an AZT-resistant clinical isolate in cell culture with AZT and 3TC. Genetic mapping and site-directed mutagenesis experiments demonstrated that a polymorphism at codon 333 (Gly to Glu) of human immunodeficiency virus type 1 reverse transcriptase (RT) was critical in facilitating dual resistance in a complex background of AZT and 3TC resistance mutations. To assess the potential clinical relevance of RT codon 333 changes, we studied dually resistant viruses from patients taking AZT and 3TC. Genetic mapping of RT molecular clones derived from patients' plasma samples demonstrated that in some cases polymorphism at codon 333 was responsible for facilitating dual resistance.
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PMID:A novel polymorphism at codon 333 of human immunodeficiency virus type 1 reverse transcriptase can facilitate dual resistance to zidovudine and L-2',3'-dideoxy-3'-thiacytidine. 957 80

Hepatitis B viruses establish a chronic, productive, and noncytopathic infection of hepatocytes. Viral products are produced by transcription from multiple copies (5-50) of covalently closed circular (ccc) viral DNA. This cccDNA does not replicate, but can be replaced by DNA precursors that are synthesized in the cytoplasm. The present study was carried out to determine if long-term treatment with an inhibitor of viral DNA synthesis would lead to loss of virus products, including cccDNA, from the liver of woodchucks chronically infected with woodchuck hepatitis virus. Viral DNA synthesis was inhibited with the nucleoside analog, lamivudine (2'-deoxy-3'-thiacytidine). Lamivudine treatment produced a slow but progressive decline in viral titers in serum, to about 0.3% or less of the initial level. However, even after maintenance of drug therapy for 3-12 months, > 95% of the hepatocytes in most animals were still infected. Significant declines in the percentage of infected hepatocytes and of intrahepatic cccDNA levels were observed in only three woodchucks, two in the group receiving lamivudine and one in the placebo control group. Moreover, virus titers eventually rose in woodchucks receiving lamivudine, suggesting that drug-resistant viruses began to spread through the liver starting at least as early as 9-12 months of treatment. Three types of mutation that may be associated with drug resistance were found at this time, in a region upstream of the YMDD motif in the active site of the viral reverse transcriptase. The YMDD motif itself remained unchanged. Not unexpectedly, the lamivudine therapy did not have a impact on development of liver cancer.
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PMID:Lamivudine therapy of WHV-infected woodchucks. 961 64

Cirrhosis and hepatocellular carcinoma occur as long-term complications of chronic hepatitis B virus (HBV) infection. Antiviral therapy is potentially a successful approach for the treatment of patients with HBV infection, which includes the nucleoside analog, lamivudine [(-)2'-deoxy-3'-thiacytidine, 3TC]. Although resistance to lamivudine therapy has been reported in several HBV-infected patients, the pattern of resistance-associated mutations in HBV has not been fully characterized. We report a DNA sequence database that includes a 500-base pair region of the HBV polymerase gene from 20 patients with clinical manifestations of lamivudine resistance. Analysis of the database reveals two patterns of amino acid substitutions in the tyrosine, methionine, aspartate, aspartate (YMDD) nucleotide-binding locus of the HBV polymerase. HBV DNA from the sera of patients in Group I exhibits a substitution of valine for methionine at residue 552, accompanied by a substitution of methionine for leucine at residue 528. Patients in Group II had only an isoleucine-for-methionine substitution at position 552. Reconstruction of these mutations in an HBV replication-competent plasmid was performed in a transient transfection cell assay to determine the function/relevance of these mutations to lamivudine resistance. Both Group I and Group II mutations resulted in a substantial decrease in sensitivity to lamivudine treatment (> 10,000-fold shift in IC50 over wild-type [wt] IC50), strongly indicating that these mutations were involved in resistance to lamivudine. A hypothetical model of the HBV reverse transcriptase has been generated for further study of the role of these mutations in lamivudine resistance.
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PMID:Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. 962 Mar 41

The appearance in the clinic of two to three new antiretroviral agents yearly since 1995 has permitted unprecedented advances in HIV treatment. This remarkable pace of drug development is a testimony to an extraordinary international effort involving scientists, clinicians, governments, community activists and industry dedicated to the rapid and safe development of novel therapies. New drugs present the opportunity to improve HIV therapy. They also create an enormous challenge to the clinician, who must constantly assimilate data on new drugs and incorporate this information into practical management strategies. Combination therapy has proven the most effective approach to treat HIV disease. The profound and sustained viral suppression achievable with combinations such as indinavir (IDV), lamivudine (3TC) and zidovudine (ZDV) have resulted in a dramatic shift in HIV treatment paradigms over the last year. The full potential of combination therapy with available drugs has yet to be realized as only a limited number of the possible combinations incorporating new drugs have been fully tested. Even drugs available for many years may have untapped potential. Didanosine (ddI) and stavudine (d4T), once thought to be contraindicated in combination because of their overlapping peripheral neuropathy toxicity, have proven well tolerated and effective. Combination therapy can increase antiviral suppression, prevent drug resistance, optimize drug exposure and simplify dosing, but it can also result in pharmacologic antagonism, subtherapeutic drug concentrations and unexpected toxicities. Clinical studies have confirmed in vitro studies showing pharmacologic antagonism for the combination of ZDV and d4T. Combining protease inhibitors with each other or with non-nucleoside reverse transcriptase inhibitors is complicated by effects both classes of drugs have on drug metabolism and clearance. These observations underline the importance of carefully conducted clinical studies to characterize safety, pharmacokinetics and efficacy of combination therapies. In this review, we will first summarize the clinical profile of new drugs which either became commercially available last year [nelfinavir, nevirapine, delavirdine (DLV)] or are in the late stages of clinical development (DMP-266, abacavir and 141W94). Later we will summarize new data on nucleoside, protease inhibitor and non-nucleoside reverse transcriptase combination regimens. Finally, we will briefly mention new drugs in early stages of development.
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PMID:New antiretrovirals and new combinations. 963 99

Eleven compounds have now been licensed for the treatment of HIV (human immunodeficiency virus) infections: the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) zidovudine (ZDV, AZT), didanosine (DDI), zalcitabine (DDC), stavudine (D4T) and lamivudine (3TC), the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine and delavirdine, and the protease inhibitors saquinavir, ritonavir, indinavir and nelfinavir. Several other compounds that interact with the reverse transcriptase or protease or other targets of the viral replication cycle are in clinical or preclinical development. High expectations are vested in the acyclic nucleoside phosphonates PMEA and PMPA (which have proved clearly efficacious against HIV infections in phase II/III and phase I/II trials, respectively) and the bicyclam derivatives, which have recently been shown to block HIV infection through interference with the viral co-receptor CXCR4 (fusin). It has become increasingly clear that only the concomitant use of several anti-HIV agents combined can completely suppress HIV replication and offer the potential for a complete cure. To this end, the different compounds should be administered from the start at sufficiently high doses, and treatment should be started as soon as possible after the infection. Under these conditions, HIV-drug resistance development could be prevented, and progression to AIDS, arrested. Whether this procedure would also be able to eradicate the virus from the organism still needs to be proven.
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PMID:New perspectives for the treatment of HIV infections. 964 21

We compared the line probe assay (LiPA) to sequence analysis for the detection of mutations conferring resistance to nucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Plasma samples from 40 patients who had received zidovudine, dideoxyinosine, and dideoxycytosine, alone or in combination, and who were enrolled in the ALTIS 2 clinical trial (lamivudine [3TC] plus stavudine) were tested at enrollment and at week 24. RT PCR products from plasma were used for LiPA, and DNA was used for sequence analysis. LiPA gave uninterpretable results for 8.5% of the analyzed codons corresponding to 63 samples, mainly for codons 41, 69, and 70. Several minor discrepancies between the two methods occurred, mainly due to the ability of LiPA to detect mixed populations while sequence analyses detect a single homogeneous population. LiPA is suitable for detecting mixed populations and easy to implement in clinical laboratories and might be useful for epidemiological surveys of primary HIV-1 resistance.
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PMID:Line probe assay for detection of human immunodeficiency virus type 1 mutations conferring resistance to nucleoside inhibitors of reverse transcriptase: comparison with sequence analysis. 965 Sep 87

Hepatitis B virus (HBV) is the leading cause of chronic hepatitis throughout the world. Notwithstanding the availability of a safe and effective vaccine, the world prevalence of HBV has not declined significantly, thus resulting in the need for a selective antiviral agent. HBV is a small, partially double-stranded DNA virus which replicates through an RNA intermediate. Most efforts to develop anti-HBV agents have been targeted to the viral DNA polymerase which possesses reverse transcriptase activity. Currently, the most promising anti-HBV agents are nucleoside analogs which interfere with viral DNA replication. Although earlier nucleoside analogs such as vidarabine (ara-A) and fialuridine (FIAU) have displayed unacceptable toxicities, newer analogs such as lamivudine (3TC), bis-POM PMEA (GS-840), lobucavir, and BMS-200,475 have demonstrated clinical utility. In particular, the use of lamivudine has generated considerable interest in the development of other L-enantiomeric nucleoside analogs for use against HBV. Here, we provide an overview of HBV structure and replication strategy and discuss the use of cell culture systems, in vitro viral polymerase systems, and animal models to identify and evaluate anti-HBV agents. We also discuss the various classes of nucleoside analogs in terms of structure, mechanism of action, status in clinical development, ability to select for resistant HBV variants, and use in combination therapies. Finally, we present a discussion of novel antiviral approaches, including antisense and gene therapy, and address the various challenges to successful anti-HBV chemotherapeutic intervention.
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PMID:The identification and development of antiviral agents for the treatment of chronic hepatitis B virus infection. 967 Jul 81

A high-performance liquid chromatographic method for the quantitative determination of the HIV reverse transcriptase inhibitor lamivudine ((-)-2'-deoxy-3'-thiacytidine, 3TC, Epivir) in human plasma, saliva and cerebrospinal fluid is described. Lamivudine was extracted from samples using silica extraction columns prior to reversed-phase high-performance liquid chromatography with ultraviolet detection at 270 nm. The method has been validated over the range of 10 (lower limit of quantitation) to 5000 ng/ml using a 0.5-ml sample volume. Between-day and within-day precisions ranged from 3.5 to 9.0%. The assay has been used for the quantitative analysis of lamivudine in plasma and cerebrospinal fluid of HIV-1 infected patients.
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PMID:Quantitative determination of (-)-2'-deoxy-3'-thiacytidine (lamivudine) in human plasma, saliva and cerebrospinal fluid by high-performance liquid chromatography with ultraviolet detection. 974 54


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