Obligate intracellular parasites from the genus Plasmodium are the agents responsible for malaria, placing an estimated 3.4 billion people at risk of the disease throughout the world [1].
Five species of Plasmodium parasites cause human malaria, yet the largest impacts to public health are primarily caused by Plasmodium falciparum in sub-Saharan Africa [2].
The emergence of drug-resistant malaria parasites has created a critical need for the discovery of novel reagents towards unexplored aspects of malaria biology. Protein-protein interactions (PPI) are necessary for any given organism to fulfill its diverse functions. These interactions have co-evolved to optimally meet certain requirements such as selectivity or specificity with varying degrees [3].
Some promiscuous proteins interact with many partner molecules and may be more difficult to target by a small molecule intervention strategy. We have focused our attention on a few selected essential proteins from Plasmodium parasites and developed methods and assays to identify PPI inhibitors as well as stabilizers [4,5], which interfere with their normal function.
Primary hits are identified using surface plasmon resonance and validated by one or more orthogonal methods such as thermal stability assay, enzyme assay, co-crystallization and in vitro parasite validation [6,7] .
Jürgen Bosch, PhD, Assistant Professor
Johns Hopkins University
Jürgen Bosch, Johns Hopkins University
Obligate intracellular parasites from the genus Plasmodium are the agents responsible for malaria, placing an estimated 3.4 billion people at risk of the disease throughout the world [1].
Five species of Plasmodium parasites cause human malaria, yet the largest impacts to public health are primarily caused by Plasmodium falciparum in sub-Saharan Africa [2].
The emergence of drug-resistant malaria parasites has created a critical need for the discovery of novel reagents towards unexplored aspects of malaria biology. Protein-protein interactions (PPI) are necessary for any given organism to fulfill its diverse functions. These interactions have co-evolved to optimally meet certain requirements such as selectivity or specificity with varying degrees [3].
Some promiscuous proteins interact with many partner molecules and may be more difficult to target by a small molecule intervention strategy. We have focused our attention on a few selected essential proteins from Plasmodium parasites and developed methods and assays to identify PPI inhibitors as well as stabilizers [4,5], which interfere with their normal function.
Primary hits are identified using surface plasmon resonance and validated by one or more orthogonal methods such as thermal stability assay, enzyme assay, co-crystallization and in vitro parasite validation [6,7] .
1. WHO (2013) World Malaria Report 2013. Geneva, World Health Organization.
2. Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI (2005) The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434: 214-217.
3. Hain AU, Bosch J (2013) Autophagy in Plasmodium, a multifunctional pathway? Comput Struct Biotechnol J 8: e201308002.
4. Boucher LE, Bosch J (2013) Development of a multifunctional tool for drug screening against plasmodial protein-protein interactions via surface plasmon resonance. J Mol Recognit 26: 496-500.
5. Boucher LE, Bosch J (2014) Structure of Toxoplasma gondii fructose-1,6-bisphosphate aldolase. Acta Crystallogr F Struct Biol Commun 70: 1186-1192.
6. Hain AU, Weltzer RR, Hammond H, Jayabalasingham B, Dinglasan RR, et al. (2012) Structural characterization and inhibition of the Plasmodium Atg8-Atg3 interaction. J Struct Biol 180: 551-562.
7. Hain AU, Bartee D, Sanders NG, Miller AS, Sullivan DJ, et al. (2014) Identification of an Atg8-Atg3 protein-protein interaction inhibitor from the medicines for Malaria Venture Malaria Box active in blood and liver stage Plasmodium falciparum parasites. J Med Chem 57: 4521-4531.