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Penn team developing new class of malaria drugs using essential calcium enzyme
Date:12/27/2012

PHILADELPHIA - Calpain, a calcium-regulated enzyme, is essential to a host of cellular processes, but can cause severe problems in its overactivated state. It has been implicated as a factor in muscular dystrophy, AIDS, Alzheimer's disease, multiple sclerosis, and cancer. As such, finding and exploiting calpain inhibitors is an important area of research.

A team from the Perelman School of Medicine, University of Pennsylvania, in collaboration with the University of California at San Francisco and the Department of Biochemistry and Protein Function Discovery at Queen's University, has developed a unique approach to calpain inhibition by mimicking a natural reaction with a synthesized molecule. The work was published in the latest issue of the Journal of the American Chemical Society.

One of calpain's less beneficial functions is that it eases the ability for cellular invaders such as the Plasmodium falciparum parasite, which is responsible for malaria, to exit their hosts and infect other cells. It is this property that caught the attention of Doron Greenbaum, PhD, assistant professor in of Pharmacology, whose laboratory studies how malaria spreads.

"We have an interest in this protein because it's important for Plasmodium development," he explains. "We initially found that calpain played a role in parasites being able to get out of their host cell, so we became interested in inhibitor development for human calpains."

Greenbaum and his collaborators examined the crystal structure of calpastatin, a natural calpain inhibitor, for clues. "We decided to take a different tack on inhibitor development, which has traditionally been designing small peptide-like inhibitors that fit across an enzyme's active site," Greenbaum says. Studying the configuration of how calpastatin bound to the active site of the calpain complex, "we found that there was a small alpha-helix that fit into the active site o
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

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