Purdue News

August 23, 1993 New compound inhibits aids virus CHICAGO–A new treatment for AIDS under development at Purdue University may someday be used to intercept the HIV virus before it attaches to a host cell, thus blocking the spread of the disease in HIV-positive patients. The treatment relies on a new compound, called cosalane, that works by preventing a vital protein on the virus from attaching to its receptor site on the cell membrane, says Mark S. Cushman, professor of medicinal chemistry. "Attachment of the virus to the cell membrane is the first event in the replication cycle of the virus," Cushman says. "If we can prevent the initial attachment, then we can prevent the virus from infecting healthy cells." He will present details of the studies at a news briefing Monday (8/23) at the American Chemical Society's annual meeting in Chicago. Acquired Immunodeficiency Syndrome, or AIDS, is caused by a virus that cripples the immune system by attacking lymphocytes, the white blood cells responsible for the immune response. The virus reproduces by first attaching and fusing with a host cell, then inserting its genetic material into the host's genome, thereby tricking the host cell into making new viruses. Cosalane uses a novel mechanism to block the replication cycle of the virus before it begins. Laboratory studies also suggest cosalane may be able to suppress AIDS virus reproduction in patients without the toxic side effects associated with current AIDS treatments. The federal government is now pushing to make the drug available for pre-clinical tests. However, researchers must clear several major hurdles before human trials can begin, including additional tests for possible side effects. The new compound was derived from research aimed at identifying nontoxic compounds with anti-AIDS activity. Cushman identified more than 1OO such compounds by chemically manipulating a polymer called ATA, or aurintricarboxylic acid. ATA once was used in the Swiss dye industry and was identified several years ago as a potential anti-AIDS drug. Though problems developed in using ATA as an AIDS therapy, Cushman and his group began searching for components of the molecule that could retain their anti-viral activity. Cosalane was developed by combining a fragment of ATA with cholestane, a steroid related to cholesterol. The cholestane fragment is used to direct the drug to the cell membrane and the surface of the virus. The drug then acts to prevent a protein on the virus surface, called gpl2O, from binding to its receptor site on the cell membrane. Laboratory tests of the compound suggest it is effective in inhibiting the attachment of both HIV- 1 and HIV-2 viruses to human lymphocytes. In addition, preliminary tests show that cosalane is highly effective in concentrations too weak to harm the cell. That's very important," Cushman says. "We want to prevent the virus from spreading without killing healthy cells." In addition to blocking the initial union between virus and cell, Cushman says, cosalane can inhibit "post-binding fusion events," the process by which the outer shell of the virus fuses with the cell membrane. Though further toxicology studies are needed, Cushman says initial studies have helped spur interest among medical researchers eager to find anti-AIDS treatments with fewer side effects. The three drugs currently available for use in combating AIDS infection–AZT, DDI and DDC–are limited by their toxic side effects. Use of AZT, for example, can result in anemia because of suppression of the bone marrow. DDI and DDC also have exhibited toxic side effects resulting in problems such as pancreatitis and disturbances of the peripheral nervous system. The drugs currently available also are limited by the emergence of drug-resistant viral strains. AZT, for example, has been shown to lose its effectiveness when used over a prolonged period of time because of the viruses' ability to mutate and eventually circumvent the drug's effects. "Because these three drugs work by a similar mechanism, we expect to see the emergence of resistant viral strains for DDI and DDC, as well," Cushman says. Another hurdle yet to clear before cosalane moves to clinical trials is finding ways to produce the drug in sufficient quantities. Though the drug is synthesized through a multi-step process at Purdue, further process development is needed to produce large quantities of the drug. Cushman says the federal government has contracted with a number of chemical manufacturing companies to address this problem. The two primary companies involved in the process are Starks Associates of Buffalo, N.Y., and Pharm-Eco Laboratories Inc. of Lexington, Mass. "At this point in our research, finding ways to synthesize the drug in large quantities would hasten the remaining pre-clinical studies and is key to making the treatment available in clinical studies," Cushman says, noting that human trials are at least one year away. The research at Purdue is supported by the National Cancer Institute through the National Institutes of Health. Cushman says he believes the new therapy may someday be used in combination with other treatrnents to combat AIDS. NOTE: Black & white photographs of Cushman in his laboratory are available from the Purdue News Service, 765-494-2O96. Contact Purdue News Service (765) 494-2096 or purduenews@purdue.edu To the Purdue News and Photos Page