Science embargo: 4 p.m. (EST) April 9, 1998
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UCSD RESEARCHERS DISCOVER NEW INHIBITOR OF MOLECULAR MOTORS
Powerful molecule comes from Pacific Ocean sponge
Researchers at University of California, San Diego (UCSD) School of Medicine and UCSD's Scripps Institution of Oceanography have identified a new inhibitor molecule that is the first to target kinesins, a large and important family of motor proteins that play a central role in intracellular transport and cell division. The new compound, called adociasulfate-2 (AS-2), is derived from a Haliclona (also called Adocia) species of marine sponge found in the western Pacific.
AS-2 not only promises to be an important tool for studying kinesins, it may also represent a gateway for improved cancer drugs in the future. The discovery is published in the April 10, 1998 issue of the journal Science.
"This is a major discovery that will aid cell biologists around the world who are trying to understand how cells divide and how they transport cargoes," said James Deatherage, Ph.D., a program director at the National Institute of General Medical Sciences, National Institutes of Health.
Kinesins, often referred to as molecular motors, move material within the cell along protein tracks called microtubules. During cell division, for example, kinesins move chromosomes into the newly forming daughter cells. Much of how this critical process works, however, is poorly understood. Inhibitor molecules are valuable because of their ability to stop the process at various intervals, providing scientists opportunity to study these points in detail and to piece the puzzle together until a picture emerges of the whole dynamic process.
"This finding is exciting because it inhibits kinesins by a completely unexpected mechanism," said the paper's senior author, Lawrence S.B. Goldstein, Ph.D., professor of pharmacology in the division of cellular and molecular medicine at UCSD School of Medicine and an investigator in the Howard Hughes Medical Institute. "In terms of potential clinical application, compounds of this type could be much more specific than currently available cancer drugs, which means it could lead to a new class of drugs with fewer and less destructive side effects."
For example, taxol is a potent inhibitor molecule that attacks microtubules. Biochemically speaking, microtubules are the same among different cell types so taxol is toxic to a variety of cells, resulting in serious side effects, such as nerve cell damage. Kinesin motors, however, differ based on cell type and function within the cell. While AS-2 was toxic to every kinesin tested, it may be feasible, say the researchers, to engineer the compound to attack some motors and not others.
The clinical possibilities will become clearer as the researchers develop a more detailed understanding of AS-2's mechanism of activity, which they hope to achieve over the next year.
This discovery is one of the latest in the rapidly emerging field of marine biomedicine. This Haliclona species looks like short lengths of pale violet rope, and is commonly referred to as a rope sponge.
Why study sponges? Chemical protection, according to co-author John Faulkner, Ph.D., professor of marine chemistry at UCSD's Scripps Institution of Oceanography.
"Organisms that appear to defend themselves chemically rather than by shells and spines, or the mobility to run away and hide, are of great interest to us, " he said. "So if we go out onto a reef and see something that looks like a large chunk of food - poorly protected, soft-bodied and easy to grab - and nothing is eating it, we assume it has chemical protection."
The underlying assumption is that some of the chemicals that help protect marine organisms also may ward off disease in humans.
"There is a sense that this compound may be the first of a new breed of pharmaceuticals," said Goldstein. "It's too soon to know how AS-2 will fare, but either way, our proof-of-principal work will launch a flurry of new scientific inquiry that we hope will lead to many more molecules with similar mechanisms of action."
Besides Goldstein and Faulkner, co-authors on the paper are Michael S. Berdelis, and postdoctoral fellows Roman Sakowicz, Ph.D., and Krishanu Ray, Ph.D., of the division of cellular and molecular medicine at UCSD School of Medicine and the Howard Hughes Medical Institute; and graduate student Christine L. Blackburn, and postdoctoral fellow Cordula Hopmann, Ph.D., at the UCSD Scripps Institution of Oceanography.
This work was funded in part by the California Sea Grant College System, the CapCure Foundation, Howard Hughes Medical Institute, and the National Institutes of Health.
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