Enzymes possible targets for new anti-malaria drugs

Researchers at the Perelman School of Medicine at the University of Pennsylvania, Monash University, and Virginia Tech have used a set of novel inhibitors to analyze how the malaria parasite, Plasmodium falciparum, uses enzymes to chew up human hemoglobin from host red blood cells as a food source. They have validated that two of these parasite enzymes called peptidases are potential anti-malarial drug targets. The research appeared in an early online edition of the Proceedings of the National Academy Sciences.

"The basis for this research was to use small to help understand the biology of the malaria parasite and to find new as drug-resistant parasites necessitate the discovery of new antimalarials," says Doron C. Greenbaum, PhD, assistant professor of Pharmacology at Penn, who lead the collaborative study.

The P. falciparum parasite, delivered in a , causes malaria once it takes up residence in the human host's and begins to digest hemoglobin, the protein that carries oxygen. The parasite multiplies and is picked up from the bloodstream when the mosquito feeds. Scientists are interested in determining which enzymes are responsible for generating amino acids from the hemoglobin in the feeding process.

Two enzymes, called aminopeptidases, have been proposed as being responsible for releasing single from proteins, or peptides. However, "there has been controversy regarding where this takes place and which enzymes are responsible," said Michael Klemba, associate professor of biochemistry with the Vector-Borne Infectious Disease Research Group at Virginia Tech, who collaborated on the evaluation of new aminopeptidase inhibitors with Greenbaum's lab. "It has been difficult to study their specific roles in breaking down hemoglobin."

The Penn team developed chemical called activity-based probes that enabled the researchers to specifically inhibit one or the other of the enzymes. "When we inhibited the parasite enzyme PfA-M1, it blocked hemoglobin degradation, starving the parasite to death. While inhibition of the leucyl aminopeptidase showed it to have an important but distinct role earlier in the parasite's life cycle within the red blood cell. Our collective data suggest that these two MAPs are both potential antiparasitic drug targets," explains Greenbaum.

"Dr. Greenbaum's team developed the probes and Virginia Tech's researchers tested the probes on purified enzymes and determined the potency of the probes against each of the two aminopeptidases," said Klemba. "Dr. Whisstock's team at Monash University did the structural biology, providing the high-resolution atomic structure of the enzymes."

Related Stories

Recommended for you

Testing time for stem cells

1 hour ago

DefiniGEN is one of the first commercial opportunities to arise from Cambridge's expertise in stem cell research. Here, we look at some of the fundamental research that enables it to supply liver and pancreatic ...

Team finds key signaling pathway in cause of preeclampsia

20 hours ago

A team of researchers led by a Wayne State University School of Medicine associate professor of obstetrics and gynecology has published findings that provide novel insight into the cause of preeclampsia, the leading cause ...

Rapid test to diagnose severe sepsis

Oct 23, 2014

A new test, developed by University of British Columbia researchers, could help physicians predict within an hour if a patient will develop severe sepsis so they can begin treatment immediately.

User comments