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Pharmaceuticals

COMPOUNDS FIGHT ARTERY NARROWING

With few side effects in mice, molecules target key atherosclerotic enzyme

by LOUISA DALTON
January 19, 2004 | APPEARED IN VOLUME 82, ISSUE 3

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Credit: 2004 NATIONAL ACADEMY OF SCIENCES
Cross section of mouse aortas shows a larger deposit in the control artery (left) compared to the beauveriolide-treated artery (right).
Credit: 2004 NATIONAL ACADEMY OF SCIENCES
Cross section of mouse aortas shows a larger deposit in the control artery (left) compared to the beauveriolide-treated artery (right).

Circular compounds from a common soil fungus show promise in treating atherosclerosis. Researchers in Japan discovered that beauveriolides I and III, 13-membered cyclic depsipeptides made of three amino acids and a fatty acid, inhibit the buildup of macrophage lipids in a mouse with atherosclerotic arteries [Proc. Natl. Acad. Sci. USA, 101, 737 (2004)]. Lipid buildup is one of the essential steps of plaque formation, which leads to artery narrowing.

The scientists further elucidated the fungal compounds' specific target: the enzyme acyl-CoA:cholesterol acyltransferase (ACAT). Coauthor Hiroshi Tomoda, a professor of lipid biochemistry at Kitasato University, notes that "ACAT plays multiple roles in our body: cholesterol absorption from the intestine, lipoprotein production in the liver, and atherosclerogenesis in the artery. Therefore, researchers believe that ACAT is an ideal target for treatment of atherosclerosis."

Other ACAT inhibitors have already been identified. The major significance of the new paper, says James E. Metherall, associate professor of human genetics at the University of Utah, "is that the beauveriolides don't seem to cause the same side effects as other ACAT inhibitors," including diarrhea and kidney tissue damage in mouse models. "This suggests that the side effects are not due to direct inhibition of ACAT" and that it might be possible to modify existing ACAT inhibitors to eliminate the side effects, Metherall says.

Statins are the current workhorse drugs for fighting fatty buildup in arteries. They block cholesterol synthesis by inhibiting HMG CoA reductase and have few side effects. Tomoda believes that identifying lead molecules for inhibiting ACAT as well will offer broader strategies for treating the complex phenomenon of atherosclerosis. The Japanese group, led by Satoshi Omura at the Kitasato Institute and Kitasato University, is now using combinatorial chemistry to screen for more potent derivatives of the natural beauveriolides.

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