Johns Hopkins Gazette: January 2, 1996

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

     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

     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

     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

     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.

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