A novel mechanism for inhibition of HIV-1 reverse transcriptase
| Autor: | Stephen H. Hughes, Dolan H. Eargle, Maxine V. Medaglia, Edward Arnold, Karl Maurer, Diana C. Roe, Robert W. Buckheit, Hong Qiang Gao, Robert J. Fisher, Angelika Muscate, A. Geoffrey Skillman, Elisabeth Davioud-Charvet, Paul L. Boyer, George L. Kenyon, Todd J. A. Ewing, Irwin D. Kuntz, Margaret J. Stauber |
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| Rok vydání: | 2002 |
| Předmět: |
DNA polymerase
Ribonuclease H Biochemistry Drug Discovery Murine leukemia virus Humans RNase H Molecular Biology Polymerase Klenow fragment chemistry.chemical_classification Binding Sites biology Chemistry Organic Chemistry biology.organism_classification Virology Molecular biology HIV Reverse Transcriptase Reverse transcriptase Kinetics Enzyme HIV-1 biology.protein Reverse Transcriptase Inhibitors Nucleoside Algorithms |
| Zdroj: | Bioorganic Chemistry. 30:443-458 |
| ISSN: | 0045-2068 |
| Popis: | The human immunodeficiency virus (HIV) epidemic is an important medical problem. Although combination drug regimens have produced dramatic decreases in viral load, current therapies do not provide a cure for HIV infection. We have used structure-based design and combinatorial medicinal chemistry to identify potent and selective HIV-1 reverse transcriptase (RT) inhibitors that may work by a mechanism distinct from that of current HIV drugs. The most potent of these compounds (compound 4 , 2-naphthalenesulfonic acid, 4-hydroxy-7-[[[[5-hydroxy-6-[(4-cinnamylphenyl)azo]-7-sulfo-2-naphthalenyl]amino]carbonyl]amino]-3-[(4-cinnamylphenyl)azo], disodium salt) has an IC 50 of 90 nM for inhibition of polymerase chain extension, a K d of 40 nM for inhibition of DNA–RT binding, and an IC 50 of 25–100 nM for inhibition of RNaseH cleavage. The parent compound ( 1 ) was as effective against 10 nucleoside and non-nucleoside resistant HIV-1 RT mutants as it was against the wild-type enzyme. Compound 4 inhibited HIV-1 RT and murine leukemia virus (MLV) RT, but it did not inhibit T 4 DNA polymerase, T 7 DNA polymerase, or the Klenow fragment at concentrations up to 200 nM. Finally, compound 4 protected cells from HIV-1 infection at a concentration more than 40 times lower than the concentration at which it caused cellular toxicity. |
| Databáze: | OpenAIRE |
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