Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine), an inhibitor of glycoprotein processing, has been shown to inhibit the human immunodeficiency virus type 1 (HIV-1) with acceptable toxicity in cultured cells. In contrast to reverse transcriptase inhibitors, castanospermine targets host enzymes. We have analyzed castanospermine in murine systems, using cultured cells as well as live animals. Plaque formation by Rauscher murine leukemia virus (RLV) was inhibited with a median inhibitory concentration (IC50) of 2 micrograms/ml. RLV-exposed BALB/c mice treated with a 20 day course of castanospermine starting 4 h postinoculation showed a dose-dependent inhibition of splenomegaly. Oral castanospermine therapy given to chronically RLV-infected mice prolonged median survival from 36 to 94 days when compared to untreated controls (p = 0.007). Castanospermine was better tolerated orally than intraperitoneally at the same dose. Toxic effects included weight loss, lethargy, and dose-dependent thrombocytopenia. At the highest intraperitoneal dose, lymphoid depletion occurred in thymus, spleen, and lymph nodes. We conclude that castanospermine is an active antiviral agent in animals and that prolonged oral administration is tolerable; however, when compared to 3'-azido-3'-deoxythymidine in the same murine system, castanospermine was less active and more toxic.
 ...
PMID:In vivo analysis of castanospermine, a candidate antiretroviral agent. 249 48

The replicative cycle of the human immunodeficiency virus (HIV) is reviewed, and currently used and investigational agents directed against the virus are discussed. The first step in the replication of HIV is selective binding of the envelope glycoprotein to CD4 receptors located on T lymphocytes. The virion is then uncoated within the cytoplasm, yielding viral genomic RNA. Reverse transcriptase uses the viral RNA as a template to form single-stranded DNA, which is duplicated to form proviral DNA through the activity of ribonuclease H. Host RNA polymerases transcribe the integrated proviral DNA into messenger RNA, and there is subsequent translation to viral proteins. After translation, further modification of precursor polyproteins is necessary to produce functional peptides. The assembled virus then buds from the cell surface and invades other cells. Targets of drug intervention in the replicative cycle include (1) binding and entry, (2) reverse transcriptase, (3) transcription and translation, and (4) viral maturation and budding. Inhibitors of binding and entry include recombinant soluble CD4, immunoadhesins, peptide T, and hypericin. Nucleoside reverse-transcriptase inhibitors include zidovudine, didanosine, zalcitabine, and stavudine. Foscarnet, tetrahydroimidazobenzo-diazepinthione compounds, and nevirapine are some nonnucleoside reverse-transcriptase inhibitors. Inhibitors of transcription and translation include antagonists of the tat gene and GLQ223. Castanospermine, N-butyldeoxynojirimycin, and protease inhibitors interfere with viral maturation and budding. Drug combinations that have been or are being investigated include zidovudine plus interferon alfa, zidovudine plus zalcitabine, and zidovudine plus didanosine. Four agents currently have approved labeling for use against HIV infection: zidovudine, didanosine, zalcitabine, and stavudine. Monotherapy with zidovudine remains the treatment of first choice. Although progress has been made in developing drug therapies for HIV infection, more selective and more potent drugs are urgently needed. The best approach at present is to optimize the use of available agents, continue to investigate new therapies, and educate the public about prevention.
 ...
PMID:Agents for treating human immunodeficiency virus infection. 775 75