title: Inhibition of protein synthesis and malaria parasite development by drug targeting of methionyl-tRNA synthetases.
abstract: Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes that couple cognate tRNAs with amino acids to transmit genomic information for protein translation. The Plasmodium falciparum nuclear genome encodes two P. falciparum methionyl-tRNA synthetases (PfMRS), termed PfMRS(cyt) and PfMRS(api). Phylogenetic analyses revealed that the two proteins are of primitive origin and are related to heterokonts (PfMRS(cyt)) or proteobacteria/primitive bacteria (PfMRS(api)). We show that PfMRS(cyt) localizes in parasite cytoplasm, while PfMRS(api) localizes to apicoplasts in asexual stages of malaria parasites. Two known bacterial MRS inhibitors, REP3123 and REP8839, hampered Plasmodium growth very effectively in the early and late stages of parasite development. Small-molecule drug-like libraries were screened against modeled PfMRS structures, and several "hit" compounds showed significant effects on parasite growth. We then tested the effects of the hit compounds on protein translation by labeling nascent proteins with (35)S-labeled cysteine and methionine. Three of the tested compounds reduced protein synthesis and also blocked parasite growth progression from the ring stage to the trophozoite stage. Drug docking studies suggested distinct modes of binding for the three compounds, compared with the enzyme product methionyl adenylate. Therefore, this study provides new targets (PfMRSs) and hit compounds that can be explored for development as antimalarial drugs.
authors.affiliation: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors.forename: Tahir
authors.initials: T
authors.lastname: Hussain
authors.affiliation: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors.forename: Manickam
authors.initials: M
authors.lastname: Yogavel
authors.affiliation: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India amit.icgeb@gmail.com.
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D003198:Computer Simulation; D003593:Cytoplasm / Q000378:metabolism; D003959:Diamines / Q000494:pharmacology; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000235:genetics; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D001578:Benzopyrans; D003959:Diamines; D011500:Protein Synthesis Inhibitors; C541771:REP 3123; C533960:REP8839; D013876:Thiophenes; D008718:Methionine-tRNA Ligase