Making moves on malaria: Protein interaction networks provide clues to drug targets

SALT LAKE CITY, Utah—In two papers published back-to-back in Nature, researchers at Prolexys Pharmaceuticals, Seattle's Howard Hughes Medical Institute, and the University of California, San Diego (UCSD) elucidated and characterized the first large-scale protein interaction network of the major parasite that causes malaria, Plasmodium falciparum.

 

Already, the data is providing key insights into the metabolic and infectious pathways of a parasite that causes up to 2.7 million deaths each year worldwide, offering scientists potential drug targets. There is hope the data will also offer companies a more cost-efficient method to develop drugs which would make it easier to sell them in the the developing world.

 

In the first study, researchers at Prolexys and HHMI used a proprietary high-throughput yeast 2-hybrid assay (HyNet) to identify interacting parasite proteins. In the process, they generated maps for a number of metabolic systems, such as gene expression, host-cell invasion, DNA modification, and signal transduction, which will provide a better understanding of the parasite's life cycle and the progression of malaria within human hosts.

 

"We focused on mixed intra-erythrocytic stage parasites, the stage responsible for pathogenesis in humans," explains Prolexys CSO Dr. Sudhir Sahasrabudhe. "This allowed us to examine interactions between parasite proteins involved in invading the human cells. As a result of utilizing this approach, the proteins expressed exclusively in the liver, gametocyte, or mosquito stages are under-represented in our dataset."

 

The study was a bit of a departure for Prolexys which has focused its own drug discovery efforts on cancer and cardiovascular disease.

 

"To maintain and demonstrate its competitive edge in this technology space, the company seeks funding in other areas of biology where protein-protein interaction discovery can advance the understanding of a particular disease with unmet medical need," Sahasrabudhe says. "The Plasmodium interactome data is available in public domain. Prolexys has no internal programs in malaria drug discovery."

 

In the second study, researchers at UCSD further analyzed this data by comparing the parasite's interaction networks with those of other pathogenic or eukaryotic organisms using a program called NetworkBLAST.

 

"There have been large-scale studies to understand this parasite, including the sequencing of its genome, but almost 60% of its proteins remain uncharacterized as they do not possess significant sequence similarity with any of the known proteins across species," says Silva Suthram, a member of the USCD team. "So, when our collaborators at [HHMI] and Prolexys made the large-scale interaction network for this parasite available to us, we wanted to explore the fact that combining and comparing the protein sequence and interaction information might provide us more insight and understanding into the functioning of the parasite."

 

The California researchers identified 29 different complexes in Plasmodium that were unique to the parasite. As Suthram explains it, these complexes are prime targets for drug development as compounds that affect these systems are less likely to trigger similar effects in humans.

 

The researchers may also have improved their understanding of the growing problem of drug resistance in the parasites. One of the complexes they identified in the parasite had a counterpart in yeast, where the proteins are involved in how cells take up compounds from their environment. Modulators of one of the proteins involved in endocytosis have been shown to impact the efficacy antimalarial drugs, so further research in this area may help reverse the resistance or provide drugs with improved efficacy.

 

"The proteins involved in these interactions need to be validated in a suitable disease model," says Sahasrabudhe. "The validated targets may lead to small molecules that inhibit the expression or function of the key Plasmodium protein(s) involved in the human disease."