On Research: AIDS-fighting chemical may exist in creosote bush Emil Venere --------------------------------------- Homewood News and Information Native Americans have long been aware of the medicinal uses of the creosote bush, which grows in the southwestern United States. Now Hopkins scientists have discovered a potential AIDS-fighting chemical in the creosote bush--bolstering research findings in Australia that exposed a possible Achilles heel in the virus. The chemical, tested in cell cultures and in blood contaminated with the human immunodeficiency virus, prevented HIV from being copied inside the human chromosomes, effectively halting its replication. It does so apparently by distorting a portion of the virus's DNA, the same piece of viral DNA that may be naturally deformed in a strain of HIV that does not make people sick. The work still is in its early stages but may one day have clinical value, said Ru Chih C. Huang, the Hopkins biology professor who is leading the research. Scientists are beginning to study the chemical's effects in mice containing HIV-infected human cells. The chemical belongs to a group of compounds called lignans, which exhibit a wide range of biological properties, including antiviral action. The scientific name of the compound is 3-0-methyl nordihydroguaiaretic acid, or 3-0-methyl NDGA. Its potential AIDS application was discovered by Huang, postdoctoral fellow John N. Gnabre, a pharmacologist by training, and several members of Huang's laboratory. Here is how it works: When a person is infected with HIV, the virus attaches itself to a protein-carbohydrate structure called CD4, located on the surfaces of immune system cells called T-cells. The virus enters the cell and its RNA makes copies of DNA so that it can bind with the human chromosomes, in essence becoming part of the human DNA. Then, in a key step vital to the virus's production in human cells, a human protein called Sp1 attaches to the two ends of the viral DNA; the end pieces of viral DNA are called the LTR regions, for "long terminal repeat." After the Sp1 protein binds to the viral DNA, the virus's DNA sequence is again copied, making viral RNA. The viral RNA then undergoes a series of steps, moving outside of the cell's nucleus and into the cytoplasm, where more AIDS virus is manufactured. Huang had been studying HIV transcription and was searching specifically for compounds that might affect the Sp1-binding step. That step is essential for transcription of HIV; without it the virus cannot be produced in human cells. She tested lignans in the creosote bush because she was curious about its medicinal reputation. The creosote-derived compound, also contained in other plants, interferes with the Sp1 binding, preventing transcription. The chemical apparently attaches to a portion of the viral DNA in the general region of the Sp1-binding site, possibly distorting the DNA structure so that the Sp1 cannot bind to the DNA. Scientific papers on the research were published in November issues of Proceedings of the National Academy of Sciences and a British publication, the Journal of Tetrahedron. Another paper about the work will be published on Jan. 8 in the Journal of Chromatography. The discovery comes as scientists in Australia have found a strain of AIDS virus that does not make people sick. The HIV strain has abnormalities in the same general region of its DNA that is affected by the creosote compound, lending sup-port to the hypothesis that the LTR region is essential for making the AIDS virus a killer. "The importance of LTR in patho-genesis is supported by this work," Huang said. Native Americans have used leaves from the strongly scented olive-green creosote bush to treat a variety of health problems, boiling its leaves and branches to make a liniment for bruises and rheumatism. The Pima and Maricopa Indians boiled the branches, producing a hot tonic for stomach trouble and diarrhea. They treated toothache pain by sharpening young creosote branches, heating them in a fire and inserting them into cavities. They also used an extract, called Sonora gum, to treat a variety of respiratory ailments such as bronchitis and the common cold. Creosote's medicinal lore notwithstanding, all plants contain lignans, and many probably contain 3-0-methyl NDGA, Huang said. Her team just happened to find the HIV-fighting lignan in creosote, and scientists are now able to make the chemical synthetically. Gnabre stressed that the crude creosote leaf extract can be toxic to the liver. He said people should not try to treat themselves with the unpurified material, both because of its toxicity and because scientists have not yet conducted human research with 3-0-methyl NDGA.
Go to Gazette Homepage