Structural analyses of the malaria parasite aminoacyl‐tRNA synthetases provide new avenues for antimalarial drug discovery

• Published in: Protein science 2021-09, Vol.30 (9), p.1793-1803
• Main Authors: Chhibber‐Goel, Jyoti, Yogavel, Manickam, Sharma, Amit
• Format: Article
• Language: English
• Subjects: Amino Acyl-tRNA Synthetases - antagonists & inhibitors; Amino Acyl-tRNA Synthetases - chemistry; Amino Acyl-tRNA Synthetases - genetics; Amino Acyl-tRNA Synthetases - metabolism; aminoacyl‐tRNA synthetase; antimalarial; Antimalarials - chemistry; Antimalarials - pharmacology; Catalytic Domain; drug; Drug development; Drug Discovery; Drug resistance; Drugs; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Erythrocytes; Gene Expression; Genomes; Health risks; Humans; Lysine-tRNA Ligase - antagonists & inhibitors; Lysine-tRNA Ligase - chemistry; Lysine-tRNA Ligase - genetics; Lysine-tRNA Ligase - metabolism; Malaria; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Models, Molecular; Parasites; Phenylalanine-tRNA Ligase - antagonists & inhibitors; Phenylalanine-tRNA Ligase - chemistry; Phenylalanine-tRNA Ligase - genetics; Phenylalanine-tRNA Ligase - metabolism; plasmodia; Plasmodium falciparum - chemistry; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Plasmodium falciparum - genetics; Protein Binding; Protein biosynthesis; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein synthesis; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - chemistry; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Review; Reviews; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Therapeutic targets; tRNA; Vector-borne diseases
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.4148

Malaria is a parasitic illness caused by the genus Plasmodium from the apicomplexan phylum. Five plasmodial species of P. falciparum (Pf), P. knowlesi, P. malariae, P. ovale, and P. vivax (Pv) are responsible for causing malaria in humans. According to the World Malaria Report 2020, there were 229 million cases and ~ 0.04 million deaths of which 67% were in children below 5 years of age. While more than 3 billion people are at risk of malaria infection globally, antimalarial drugs are their only option for treatment. Antimalarial drug resistance keeps arising periodically and thus threatens the main line of malaria treatment, emphasizing the need to find new alternatives. The availability of whole genomes of P. falciparum and P. vivax has allowed targeting their unexplored plasmodial enzymes for inhibitor development with a focus on multistage targets that are crucial for parasite viability in both the blood and liver stages. Over the past decades, aminoacyl‐tRNA synthetases (aaRSs) have been explored as anti‐bacterial and anti‐fungal drug targets, and more recently (since 2009) aaRSs are also the focus of antimalarial drug targeting. Here, we dissect the structure‐based knowledge of the most advanced three aaRSs—lysyl‐ (KRS), prolyl‐ (PRS), and phenylalanyl‐ (FRS) synthetases in terms of development of antimalarial drugs. These examples showcase the promising potential of this family of enzymes to provide druggable targets that stall protein synthesis upon inhibition and thereby kill malaria parasites selectively.