Intracellular feeding of Plasmodium parasites: Characterization and inhibition of the interaction between falcipain-2 and hemoglobin

• Applicant: Professor Dr. Rolf Hilgenfeld
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2006 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 29227179

Falcipain-2 is an essential cysteine proteinase in the malaria parasite, Plasmodium falciparum. The enzyme is responsible for the degradation of hemoglobin, a process ensuring an adequate amino acid supply for the intracellular pathogen during the intraerythrocytic stage of development. We have determined the crystal structure of the mature enzyme and shown that the hemoglobin-binding segment consists of a prominent ß-hairpin protruding from the globular enzyme into solution. We have also shown that the interaction between the two proteins is pH-dependent. It is proposed to determine crystal structures of falcipain-2 at higher resolution, of its complexes with peptides corresponding to the cleavage sites in hemoglobin and with intact hemoglobin as well as myoglobin. Also, a peptide corresponding to the hemoglobinbinding segment of falcipain will be cocrystallized with myoglobin or hemoglobin, in order to determine details of the interactions by X-ray crystallography. All crystallographic studies will be accompanied by surface plasmon resonance analysis of the interactions. This will also involve synthetic inhibitors of falcipain-2 and its interaction with hemoglobin that will be designed on the basis of the crystallographic results. This project is expected to shed light on the details of this important hostpathogen interaction and pave the way for the discovery of urgently needed new inhibitors for the treatment of malaria.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1131: Life Inside Cells