Scientists Find Promising Anti-AIDS Compound in Creosote Plant
The chemical, tested in cell cultures and in blood contaminated with the human immunodeficiency virus, prevented HIV from being transcribed -- or copied -- inside the human chromosomes, effectively halting its replication.
The work still is in its early stages but may one day have clinical value, said Ru Chih C. Huang, the Johns 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, which scientists can now synthesize, 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 the HIV virus, 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 which the virus cannot be produced in human cells.
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.
The discovery comes as scientists in Australia have discovered a strain of AIDS virus that does not make people sick. The strain has abnormalities in the same general region of its DNA that is affected by the creosote compound, lending support to the hypothesis that the LTR region is essential for making the AIDS virus a killer. "The importance of LTR in pathogenesis is supported by this work," Huang said.
The creosote bush grows wild in arid regions of the southwestern United States and of Mexico. Native Americans have used leaves from the strongly scented olive-green 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 happened to find the HIV-fighting lignan in creosote because she was curious about the plant's folkloric reputation.
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 tests with 3-0-methyl NDGA on humans.
On the next step, the studies in mice, Huang's team from the Johns Hopkins School of Arts and Sciences is collaborating with Richard Markham, an associate professor of medicine and an associate professor of molecular microbiology and immunology in the Johns Hopkins School of Hygiene and Public Health.
"Animal studies have always been a critical step in the movement of therapeutic agents from the test tube to the clinical setting," Markham said.
"The mouse studies we are conducting in collaboration with Dr. Huang should provide important information on the potential therapeutic usefulness of this agent," he said. "If 3-O-methyl NDGA is found to be effective and free of significant toxicity, the mouse studies may also indicate how it can be used most effectively to interrupt the progression of HIV infection."
Other scientists involved in the research published in the November papers were John N. Brady and Yoichiro Ito of the National Institutes of Health and Robert B. Bates of the University of Arizona.
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