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New Agent Blocks HIV Integrase, Another Target for Anti-AIDS Therapy

New Agent Blocks HIV Integrase, Another Target for Anti-AIDS Therapy

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 23, 1995.

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 Research Institute.

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