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)

(S,S)-Isodideoxyadenosine [(S,S)-isoddA] is an anti-HIV active compound discovered in our laboratory. However, its cellular mechanism of action, particularly the critical first stage of phosphorylation, is not understood. IsoddA is not phosphorylated by adenosine kinase. Also, because it is not a substrate for adenosine deaminase, it would not be activated by the pathway taken by ddA, i. e. via 5'-nucleotidase phosphorylation of ddI and conversion of ddIMP to ddAMP. However, we have discovered that human recombinant 2'-deoxycytidine kinase (dCK) phosphorylates (S,S)-isoddA. The enzyme kinetic data revealed that the extent of monophosphorylation of this L-related nucleoside was comparable to that found with ddA. (S,S)-IsoddATP is among the most potent inhibitors of HIV reverse transcriptase known, which suggests that the observed low efficiency of phosphorylation of this compound by dCK is a key factor that limits the capacity of human lymphocytes to make (S,S)-isoddA an exceptionally active anti-HIV agent.
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PMID:Phosphorylation of the anti-HIV compound (S,S)-isodideoxyadenosine by human recombinant deoxycytidine kinase. 1102 Apr 53

Drug combinations that include nucleoside reverse transcriptase inhibitors (NRTIs) are remarkably effective in preventing maternal-viral transmission of HIV during pregnancy. However, there may be potential long-term risks for children exposed in utero. Examination of the genotoxic and mutagenic effects of two NRTIs, zidovudine [AZT (3'-azido-3'-deoxythymidine)] and didanosine [ddI (2',3'-dideoxyinosine)], in cultured human lymphoblastoid cells revealed multiplicative synergistic enhancement of AZT-DNA incorporation and mutant frequency induction in response to the combined drug exposure, as compared with single-drug exposures. Dose-related increases in DNA incorporation of AZT (as measured by a competitive RIA) and mutagenicity at the HPRT and TK loci (as assessed by cell-cloning assays) were observed in cells exposed in culture to AZT, or equimolar combinations of AZT + ddI, at exposure concentrations ranging from 3 to 30 times the maximum plasma levels found in humans. Because mutagenesis is strongly associated with tumor induction in experimental models, children exposed transplacentally to combinations of NRTIs may be at risk for cancer development later in life.
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PMID:Zidovudine-didanosine coexposure potentiates DNA incorporation of zidovudine and mutagenesis in human cells. 1105 53

Broad use of antiretroviral drugs is becoming a factor that is important to consider for understanding the HIV-1 epidemiology. Since 1993, we observe that a proportion of new infections within major risk groups in Amsterdam is caused by azidothymidine (AZT)-resistant viruses. After the introduction of combination therapy in The Netherlands in 1997, new infections with drug-resistant viruses have not been documented. Large-scale monitoring of anti-HIV-1 therapy failures revealed that antiretroviral drugs may yield previously undescribed resistant viruses, which contain a two amino acid insertion (68SS/V69) within their reverse transcriptase genes in combination with mutations at codons 67 and 215. These viruses are highly resistant to AZT, 3TC, and d4T, and moderately resistant to ddI and ddC.
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PMID:Epidemiology of HIV-1 and emerging problems. 1111 59

Stavudine, 2',3'-didehydro-3'deoxy thymidine (d4T) has been approved by the Food and Drug Administration and is the fourth commercially available drug in the nucleoside analog reverse transcriptase class. d4T is used in the treatment of advanced HIV-1 infection in patients: 1) who are AZT, ddI or ddC intolerant; 2) who have experienced significant clinical or immunologic deterioration or 3) for whom other therapies are contraindicated. It is thought to work like other dideoxynucleoside compounds by inhibiting HIV-1 replication. There is little or no evidence of resistance and it has been demonstrated to work synergistically with ddI and ddC against HIV-1 in vitro. Clinical trials in a total of 272 patients show that doses of 0.5 to 1.0 mg/kg/day provide the best therapeutic/toxicity ratio. Sustained changes in surrogate markers have included increases in CD4 counts, decreases in serum p24 antigen and decrease in virus load measures. Other data show significant weight gain in patients receiving d4T and more favorable quality of life, compared to AZT treatment. The major toxicity is peripheral neuropathy. The recommended dose of d4T for clinical practice is 40 mg orally twice daily and the cost is slightly less than AZT.
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PMID:FDA approves d4T as alternative to AZT, ddI, or ddC. Food and Drug Administration. 1136 62

Patients taking a triple combination of AZT, ddI, and nevirapine appear to have better surrogate markers than those taking the double combination of AZT and ddI, according to 241 AIDS Clinical Trials Group (ACTG) researchers. The triple combination resulted in a 40 percent increase in T-cells over baseline, which persisted through 40 weeks of the study. The triple combination also produced greater decreases in the viral load. Although the trial was not designed to evaluate clinical endpoints, there appeared to be no difference in clinical endpoints except in patients with fewer than 50 T-cells or where there was a trend toward fewer clinical endpoints with the triple combination. Nevirapine, an investigational nonnucleoside reverse transcriptase, is available only through clinical trials.
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PMID:Triple combination superior to double combination. 1136 10

Researchers at the National Institutes of Health (NIH) continue to study the use of the FDA-approved anticancer drug hydroxyurea (HU) as an inhibitor of viral reverse transcriptase for the treatment of HIV infection. Rather than targeting HIV itself, HU targets the cells in which viral replication takes place, which reduces the chances of resistant mutants appearing. In addition to having low toxicity, HU appears synergistic with nucleoside analogues such as AZT, ddI, and ddC. Safety, efficacy, and dosage of HU have not been established for patients with HIV.
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PMID:Hydroxyurea under study. 1136 69

The debate of monotherapy vs. combination therapy during the July 25th-27th Consensus Symposium on Combined Antiviral Therapy is discussed. Specific topics addressed at the Lisbon conference included whether the protease inhibitor, indinavir, could antagonize the effects of ZDV plus 3TC; synergy claimed with VX-478 and ZDV, ddI, and other reverse transcriptase inhibitors; a proposal that ablative therapy against HIV during the first weeks of infection could become a reasonable tactic when patients are diagnosed very early; a discussion of recent data suggesting that cross-resistance of HIV to several protease inhibitors is not an insurmountable problem and that convergent therapy with the drugs remains a possibility; and indications that HIV doubly resistant to 3TC and ZDV can emerge, at least when 3TC is started first and ZDV is added later.
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PMID:A Lisbon traviata. Are clinicians ready to sing addio to monotherapy and libiamo to combinations? 1136 92

Newly publicized trial data are showing that hydroxyurea has strong anti-HIV activity, especially when combined with ddI, which has led to the opening of new trials testing the hydroxyurea/ddI combination. Hydroxyurea's purported mechanism of action against HIV is to inhibit a cellular enzyme, ribonucleotide reductase, that is essential for creating the special nucleotide units needed to form DNA. With fewer natural DNA nucleotides present, HIV's reverse transcriptase enzyme may be more likely to incorporate nucleoside analog compounds, such as AZT or ddI, into the DNA it is creating from HIV's RNA gene template. These nucleoside analogs are defective versions of the natural building blocks and force the viral DNA chain under construction to terminate prematurely. Additional information from various studies and new trials opening in the U.S. and abroad are provided.
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PMID:New data intensifies interest in hydroxyurea. 1136 2

A clinical trial, protocol ICC-002, is comparing three anti-HIV treatment regimens: 1) AZT and ddI; 2) AZT, ddI, and 3TC; and 3) AZT, ddI, and nevirapine (an experimental non-nucleoside reverse transcriptase inhibitor). The Inter-Company Collaboration for AIDS Drug Development will enroll 225 participants with CD4 counts between 200 and 500, who have not previously used antiretrovirals. The study will compare the effects of these treatments on viral load, CD4 count, and other disease progression markers.
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PMID:New double vs. triple antiviral combination study, CD4 200-500, no prior treatment. 1136 52

The Retroviruses Conference and Immune-Based Therapies Workshop held in 1996 presented encouraging clinical findings in the management of HIV infections, but unanswered questions persist. A summary and analysis are presented of the workshop's findings and questions still needing to be addressed. Areas discussed include the prospects of quadruple combination therapy; additional data showing the merits of nucleoside analog reverse transcriptase inhibitors; a study showing hydroxyurea boosts ddI effect; the prospects of new antiretrovirals such as delavirdine, nevirapine, adefovir, and 1592U89; the power of monitoring viral load; and pediatric antiretroviral strategies. Final discussions address the immune system's ability to restore itself after repeated long-term antiretroviral therapies.
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PMID:Six days inside the beltway--and most AIDS clinicians still come out smiling. 1136 26


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