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

March 1, 1996

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.

Researchers at Aronex Pharmaceuticals, the Katholieke UniversiteitLeuven, the National Cancer Institute, the University of Californiaat San Francisco, and the Southern Research Institute reportedlaboratory results indicating that AR-177, a new anti-HIV drug,inhibits viral production through a pathway distinct from otherestablished and experimental approaches. The studies were reportedin the November 1995 issue of Antimicrobial Agents and Chemotherapy.

"Among the more pressing needs in the area of HIV therapyare compounds that act against new viral targets," remarkedMichael McGrath, MD, PhD, a coauthor of the study. "AR-177appears to block the viral activity of HIV integrase rather thanreverse transcriptase or HIV protease. This activity may be complementaryto compounds that operate by inhibiting these commonly targetedenzymes." Dr. McGrath, who is Associate Professor of LaboratoryMedicine at the University of California at San Francisco, cautionedthat these laboratory results are still early and must be confirmedin clinical tests, which have just recently begun.

HIV integrase is an enzyme that HIV-1 uses to insert its replicatedgenetic material (DNA) into the host chromosome or DNA. In thenew studies, the collaborating researchers demonstrated that AR-177inhibits this enzyme. Most other HIV therapeutic drugs act byinhibiting either viral reverse transcriptase, which HIV-1 usesto replicate its genetic code, or viral protease, which the virususes to make its protective protein coat.

AR-177 is a short oligonucleotide made up entirely of the nucleotidesdeoxyguanosine and thymidine linked by a phosphodiester backbone.Inter-nucleoside bonds at the two ends of the molecule are chemicallymodified to help stabilize the compound against attack by cellularenzymes. The molecule also folds itself into a defined three-dimensionalstructure, which gives AR-177 its potent activity.

The researchers infected several types of cells, including peripheralblood cells (mononuclear cells and leukocytes) and several laboratorycell lines, with HIV-1. The cells were treated with either zidovudine(AZT [Retrovir] or AR-177. The cell cultures were then analyzedfor viral proliferation at various lengths of time by measuringboth the levels of viral p24 antigen production in the culturemedium or the amount of intracellular viral DNA. The effect ofAR-177 on peripheral blood leukocytes was also analyzed by measuringtheir levels of CD4 and CD8 antigen expression in culture.

Extended Duration of Activity

The compound's three-dimensional structure appears to contributeto its mechanism of action, long half-life, and extended durationof activity. In mouse systems, AR-177 had a half-life of days.In culture assays, viral production was halted for more than 21days following 4 days of AR-177 treatment. By comparison, AZT,which has a half-life of hours, halted viral production for only2 additional days following 4-day treatment. The paper also reportedthat studies with human immune cells show no observable toxicityfrom high in vitro doses of AR-177.

"This compound is the first new molecular agent to emergefrom the Aronex research pipeline," said James Chubb, PhD,President of Aronex Pharmaceuticals. "We are focused on movingit rapidly through clinical development, and towards that endwe recently initiated a phase I study in HIV patients."

Clinical trials were begun in October by James Kahn, MD, AssociateDirector of the AIDS Program and Assistant Professor of Medicineat the University of California at San Francisco, at San FranciscoGeneral Hospital. The first clinical study is an open label, dose-escalatingtrial using single doses of AR-177 to determine the toxicity andpharmacokinetics of the compound in HIV-1-positive patients. Arepeat dose study will be started at the conclusion of the singleescalating dose trial. The first patient was dosed on October23, 1995.

The study reported in Antimicrobial Agents and Chemotherapyresulted 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 SanFrancisco and Robert Buckheit, PhD, and coworkers at the SouthernResearch Institute.