Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases

• Published in: The EMBO journal Vol. 37; no. 7
• Main Authors: Mukherjee, Budhaditya, Tessaro, Francesca, Vahokoski, Juha, Kursula, Inari, Marq, Jean‐Baptiste, Scapozza, Leonardo, Soldati‐Favre, Dominique
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.04.2018; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Antimalarials - chemistry; Antimalarials - pharmacology; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - metabolism; Aspartic Acid Proteases - antagonists & inhibitors; Aspartic Acid Proteases - metabolism; Aspartic endopeptidase; Aspartyl protease; Catalysis; Cysteine; Determinants; Dose-Response Relationship, Drug; Drug Resistance - drug effects; Drug Resistance - physiology; Egress; EMBO23; EMBO31; EMBO40; Homology; Inhibitors; Inhibitory Concentration 50; modeling; Models, Molecular; Molecular docking; Molecular Docking Simulation; Mutation; Parasite resistance; Parasites; Parasitic Sensitivity Tests; Phenylalanine; Phenylalanine - drug effects; Phenylalanine - genetics; Phylogeny; Plasmepsin; Plasmodium; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - genetics; Protease; Protease Inhibitors - pharmacology; Proteases; Proteins; Protozoan Proteins - chemistry; Protozoan Proteins - genetics; Recognition; Recombinant Proteins - genetics; Residues; Selectivity; Sensitivity; Sequence Alignment; Substrates; Toxoplasma; Toxoplasma - drug effects; Toxoplasma - genetics; Toxoplasma gondii; Tyrosine; Aspartyl protease; Plasmepsin; modeling; Toxoplasma; Plasmodium

Toxoplasma gondii aspartyl protease 3 (TgASP3) phylogenetically clusters with Plasmodium falciparum Plasmepsins IX and X (PfPMIX, PfPMX). These proteases are essential for parasite survival, acting as key maturases for secreted proteins implicated in invasion and egress. A potent antimalarial peptid...