Researchers at Aronex Pharmaceuticals, the Katholieke Universiteit
Leuven, the National Cancer Institute, the University of California
at San Francisco, and the Southern Research Institute reported
laboratory results indicating that AR-177, a new anti-HIV drug,
inhibits viral production through a pathway distinct from other
established and experimental approaches. The studies were reported
in the November 1995 issue of Antimicrobial Agents and Chemotherapy.
"Among the more pressing needs in the area of HIV therapy
are compounds that act against new viral targets," remarked
Michael McGrath, MD, PhD, a coauthor of the study. "AR-177
appears to block the viral activity of HIV integrase rather than
reverse transcriptase or HIV protease. This activity may be complementary
to compounds that operate by inhibiting these commonly targeted
enzymes." Dr. McGrath, who is Associate Professor of Laboratory
Medicine at the University of California at San Francisco, cautioned
that these laboratory results are still early and must be confirmed
in clinical tests, which have just recently begun.
HIV integrase is an enzyme that HIV-1 uses to insert its replicated
genetic material (DNA) into the host chromosome or DNA. In the
new studies, the collaborating researchers demonstrated that AR-177
inhibits this enzyme. Most other HIV therapeutic drugs act by
inhibiting either viral reverse transcriptase, which HIV-1 uses
to replicate its genetic code, or viral protease, which the virus
uses to make its protective protein coat.
AR-177 is a short oligonucleotide made up entirely of the nucleotides
deoxyguanosine and thymidine linked by a phosphodiester backbone.
Inter-nucleoside bonds at the two ends of the molecule are chemically
modified to help stabilize the compound against attack by cellular
enzymes. The molecule also folds itself into a defined three-dimensional
structure, which gives AR-177 its potent activity.
The researchers infected several types of cells, including peripheral
blood cells (mononuclear cells and leukocytes) and several laboratory
cell lines, with HIV-1. The cells were treated with either zidovudine
(AZT [Retrovir] or AR-177. The cell cultures were then analyzed
for viral proliferation at various lengths of time by measuring
both the levels of viral p24 antigen production in the culture
medium or the amount of intracellular viral DNA. The effect of
AR-177 on peripheral blood leukocytes was also analyzed by measuring
their levels of CD4 and CD8 antigen expression in culture.
Extended Duration of Activity
The compound's three-dimensional structure appears to contribute
to its mechanism of action, long half-life, and extended duration
of activity. In mouse systems, AR-177 had a half-life of days.
In culture assays, viral production was halted for more than 21
days following 4 days of AR-177 treatment. By comparison, AZT,
which has a half-life of hours, halted viral production for only
2 additional days following 4-day treatment. The paper also reported
that studies with human immune cells show no observable toxicity
from high in vitro doses of AR-177.
"This compound is the first new molecular agent to emerge
from the Aronex research pipeline," said James Chubb, PhD,
President of Aronex Pharmaceuticals. "We are focused on moving
it rapidly through clinical development, and towards that end
we recently initiated a phase I study in HIV patients."
Clinical trials were begun in October by James Kahn, MD, Associate
Director of the AIDS Program and Assistant Professor of Medicine
at the University of California at San Francisco, at San Francisco
General Hospital. The first clinical study is an open label, dose-escalating
trial using single doses of AR-177 to determine the toxicity and
pharmacokinetics of the compound in HIV-1-positive patients. A
repeat dose study will be started at the conclusion of the single
escalating dose trial. The first patient was dosed on October
The study reported in Antimicrobial Agents and Chemotherapy
resulted from the collaboration of Robert Rando, PhD, Joshua Ojwang,
PhD, and coworkers at Aronex Pharmaceuticals, Erik De Clercq,
MD, PhD, and coworkers at the Katholieke Universiteit Leuven,
Yves Pommier, MD, PhD, and coworkers at the National Cancer Institute,
Michael McGrath, MD, PhD, at the University of California at San
Francisco and Robert Buckheit, PhD, and coworkers at the Southern