Identification of Protein-Protein-Interaction (PPI) Inhibitors and Stabilizers for Antimalarial Drug Development using SPR

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Malaria has been a human life threat for centuries, particularly in tropical and subtropical regions of the world. Nevertheless, our repertoire of medication to treat the disease has been very limited 1, and emerging resistance of the malaria parasite Plasmodium has further restricted the use of current antimalarial treatment. The most recent reports indicating artemisinin resistance in Cambodia2 are indeed alarming and underscore the critical importance of exploring novel pathways for interfering with the life cycle of the malaria parasite.Surface plasmon resonance (SPR) has been a powerful tool to study protein ligand interactions. We utilize this technique for fragment and small molecule screening (∼150-500 Da) to identify PPI-inhibitors or PPI-stabilizers 3.In this study we present the identification of PPI-inhibitors for three plasmodial targets and two examples of PPI-stabilizers. We will furthermore demonstrate the in vitro effect on Plasmodium falciparum cultures of these PPI-inhibitors and PPI-stabilizers in the liver stage as well as blood stage form of the parasite. Small-molecules derived from our studies may represent useful probes for further dissecting the underlying biological mechanisms and analyzing the pathways in Plasmodium and other apicomplexan species such as Toxoplasma, Cryptosporidium, Eimeria, Theileria and Babesia. Further development of our current small molecules may provide initial hits for lead optimization in drug design studies.References1 Baird, J. K. Effectiveness of antimalarial drugs. N Engl J Med 352, 1565-1577, doi:10.1056/NEJMra043207 (2005).2 Miotto, O. et al. Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia. Nat Genet 45, 648-655, doi:10.1038/ng.2624 (2013).3 Boucher, L. E. & Bosch, J. Development of a multifunctional tool for drug screening against Plasmodial protein-protein interactions via Surface Plasmon Resonance. Journal of Molecular Recognition 26, 496-500 (2013).