University of Pennsylvania Perelman School of Medicine researchers — in collaboration with the University of California at San Francisco and the Department of Biochemistry and Protein Function Discovery at Queen’s University — have surmised a variant approach to calpain inhibition via mirroring a natural reaction with synthesized molecules.
The major implication? Such mimicry could mark the beginning of the end for malaria.
"We have an interest in this protein because it’s important for Plasmodium development," explained Doron Greenbaum, PhD, assistant professor in of pharmacology, whose laboratory studies explore how malaria spreads, in a news release. "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."
A calcium-regulated enzyme, calpain, while necessary for many processes, can also be highly contentious regarding its status as an implicate in muscular dystrophy, AIDS, Alzheimer’s disease, multiple sclerosis and cancer. Greenbaum and crew looked toward the crystal structure of calpastatin for more insight into the darker workings of calpain.
"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 said.
"Traditionally people thought that alpha-helices normally make horrible inhibitors because it was thought that proteases don't like to bind to them preferring to bind motifs called a beta-sheet. It's the first example of an alpha-helical inhibitor of any protease. Previously no one's ever tried using an alpha-helical motif. It opens up a new way of inhibiting proteases."
The researchers anticipate the next stage in their method’s development will be to expand the basic concept into a wide range of protease molecules.
“The next step is to show how this concept can be generalized to multiple classes of proteases, many of which are pharmaceutically of great interest," Greenbaum concluded. "It's not a single-hit wonder."
Furthering the technique to steady the alpha-helix shape in the given enzymes to other proteins may precede creation of practical drug therapies for a wide range of conditions.
Penn Genome Frontiers Institute, the National Institutes of Health, the Canadian Institutes for Health Research and an R.J. Wilson Fellowship all funded the research.