X-ray structures of plasmodium falciparum falcilysin in complex with novel antimalarial compounds

• Main Author: T Pravin
• Other Authors: Julien Lescar
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2023
• Subjects: Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/166915
• Institution: Nanyang Technological University

As Plasmodium falciparum malaria becomes increasingly resistant to gold-standard medical interventions including chloroquine, the situation calls for an innovative counterattack. Falcilysin (FLN), a P. falciparum protein crucial for parasite survival, has become an attractive target for synthesising novel antimalarial drugs with enhanced resistance profiles. In this project, we studied 15 potential antimalarial compounds with a view to unravel their atomic interaction between FLN and the compounds through co-crystallisation to provide significant insights into the structural basis for their mechanisms of action. Recombinant FLN plasmid was designed, transformed, and expressed in BL21(DE3) Rosetta Escherichia coli competent cells. FLN protein was then purified by nickel (II) nitriloacetate–immobilized metal affinity chromatography and size exclusion chromatography before forming protein co-crystals with the 15 compounds. The co-crystals of the compounds were subjected to X-ray crystallography and the diffraction data were processed to obtain three-dimensional (3D) electron density (ED) maps of the FLN-compound complexes. The 3D ED maps revealed the compounds’ binding sites and indicated an allosteric mode of inhibition of FLN. This work will inform the development of non-competitive antagonist drugs with increased resistance profiles to combat falciparum malaria.