• September 20, 2011
  • Enzymes Possible Targets for New Anti-Malaria Drugs, According to Penn-led Study

PHILADELPHIA —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 molecule inhibitors to help understand the biology of the malaria parasite and to find new drug targets 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 mosquito bite, causes malaria once it takes up residence in the human host's red blood cells 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 amino acids 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 genetic tools 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."

Other co-authors on the paper are first author Michael Harbut, a graduate student in the Greenbaum lab; Geetha Velmourougane, postdoctoral fellow at Penn; Seema Dalal, research scientist in biochemistry at Virginia Tech; Gilana Reiss, graduate student in Pharmacology, Penn; James C. Whisstock, Monash University, Logan Fellow and scientific director of the Victorian Bioinformatics Consortium; Ozlem Onder, postdoctoral associate in biology, and Dustin Brisson, assistant professor of biology, both at Penn; Sheena McGowan, senior research fellow at Monash University.

 

###

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.

 

 

Print, Share, or Save
 
Media Contact

Karen Kreeger
215-349-5658

 
Other Contacts
 
 
Latest News
All News Releases


About Penn Medicine   Contact Us   Site Map   Privacy Statement   Legal Disclaimer   Terms of Use

Penn Medicine, Philadelphia, PA 800-789-PENN © 2013, The Trustees of the University of Pennsylvania