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

Project: DFG ProjectsDFG Joint Research: Priority Programs

Project Details

Description

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.
Statusfinished
Effective start/end date01.01.0631.12.10

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

  • 204-03 Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology

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