Squalamine, a compound from sharks that is known for its anticancer activity, also has broad-spectrum antiviral activity, according to Michael Zasloff of Georgetown University Medical Center in Washington, D.C., and his collaborators.
Its mechanism of action helps to explain this versatility, he says.
When the cholesterol-like molecule squalamine enters cells, it displaces positively charged proteins bound to negatively charged inner cell membranes, according to Zasloff. Some viruses depend on one of those displaced cationic proteins, called Rac1, for cell entry. Meanwhile, endothelial cells in some tumors depend on vascular endothelial growth factor (VEGF) to proliferate. Coincidentally, VEGF also acts through Rac1. "Just as squalamine changes endothelial cells to become unresponsive to VEGF, it [squalamine] stops viruses from growing in other cells for the same reason," says Zasloff, who discovered the compound in 1993. "No other known compound does this."
Squalamine prevents both DNA and RNA viruses from entering host cells in vitro, and shows promising activity protecting several species of mammals against viral infections, according to Zasloff and his collaborators. For instance, the compound protects human endothelial cells against infection by dengue virus, and it blocks the hepatitis B virus in human primary hepatocytes.
When Golden Syrian hamsters are treated with squalamine one day before being infected with otherwise lethal doses of yellow fever virus, 100% of the animals survive for 9 days, whereas 85% of untreated animals were dead by day 9. When treated with the compound one day after being inoculated with yellow fever virus, 60% of animals survive, whereas none of the untreated animals survive.
Zasloff and his collaborators did other experiments to see whether squalamine protects Golden Syrian hamsters against lethal doses of Eastern equine encephalitis virus (EEEV), for which there are no effective drugs or vaccines. Squalaminetreated animals survive about a week longer than do hamsters that are untreated, and there is a 100-fold difference in their respective levels of EEEV. Squalamine also protects mice against murine cytomegalovirus (MCMV). Details appear in the September 20, 2011 Proceedings of the National Academy of Sciences [doi:10:1073/pnas.1108558108].
Because squalamine targets a host instead of a viral protein, resistance may not develop so quickly, if at all, according to Zasloff. "Squalamine changes the whole architecture of a cell, and that's harder for a virus to work around," he says. Viruses do not readily substitute other host proteins for cell entry receptors such as Rac1-or at least not very quickly. Squalamine is being evaluated in several Phase II and Phase III clinical trials involving patients either with one or another cancer or with macular degeneration, which leads to blindness. Thus, its safety profile is well understood, according to Zasloff, who plans to build on such studies to test squalamine as a treatment for viral hepatitis.
Data from the new study "is compelling for flaviviruses, and the data for hepatitis B is promising, but less developed," says Timothy Block, Director of Microbiology and Immunology at Drexel University College of Medicine in Philadelphia, Pa., and Director of the Hepatitis B Foundation. He calls Zasloff "a pioneer who has made some very provocative observations about naturally derived peptides with anti-infective properties."
Carol Potera
Carol Potera is a freelance writer in Great Falls, Mont.
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