Targeting Protein-Protein-Interactions for Antimalarial Drug Discovery

Abstract

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 (World Malaria Report 2013, WHO). 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 (Snow et al. 2005). 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. 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, 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 (Hain 2012, Hain 2014).