Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines

• Published in: Nature communications 2021-01, Vol.12 (1), p.343-10, Article 343
• Main Authors: Sharma, Manmohan, Malhotra, Nipun, Yogavel, Manickam, Harlos, Karl, Melillo, Bruno, Comer, Eamon, Gonse, Arthur, Parvez, Suhel, Mitasev, Branko, Fang, Francis G., Schreiber, Stuart L., Sharma, Amit
• Format: Article
• Language: English
• Subjects: 631/154/556; 631/326/417; 631/535/1266; 692/699/255/1629; 82/103; 82/16; 82/83; Amino Acid Sequence; Aminoacylation; Animal models; Animals; Azetidines - pharmacology; Binding sites; Catalytic Domain; Chemical synthesis; Crystal structure; Cytosol - enzymology; Disease transmission; Drug development; Drug Resistance - genetics; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humanities and Social Sciences; Inhibitors; Ligands; Malaria; Malaria - enzymology; Models, Molecular; multidisciplinary; Mutation - genetics; Parasites; Parasites - enzymology; Phenylalanine; Phenylalanine - metabolism; Phenylalanine-tRNA Ligase - antagonists & inhibitors; Phenylalanine-tRNA Ligase - chemistry; Phenylalanine-tRNA Ligase - metabolism; Plasmodium; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Prophylaxis; Protein biosynthesis; Protein synthesis; Science; Science (multidisciplinary); tRNA Phe; Vector-borne diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20478-5

The inhibition of Plasmodium cytosolic phenylalanine tRNA-synthetase (cFRS) by a novel series of bicyclic azetidines has shown the potential to prevent malaria transmission, provide prophylaxis, and offer single-dose cure in animal models of malaria. To date, however, the molecular basis of Plasmodium cFRS inhibition by bicyclic azetidines has remained unknown. Here, we present structural and biochemical evidence that bicyclic azetidines are competitive inhibitors of L-Phe, one of three substrates required for the cFRS-catalyzed aminoacylation reaction that underpins protein synthesis in the parasite. Critically, our co-crystal structure of a  Pvc FRS-BRD1389 complex shows that the bicyclic azetidine ligand binds to two distinct sub-sites within the Pv cFRS catalytic site. The ligand occupies the L-Phe site along with an auxiliary cavity and traverses past the ATP binding site. Given that BRD1389 recognition residues are conserved amongst apicomplexan FRSs, this work lays a structural framework for the development of drugs against both Plasmodium and related apicomplexans. Bicyclic azetidine inhibitors are promising antimalarials that target the Plasmodium cytosolic phenylalanine tRNAsynthetase (cFRS). Here, Sharma et al. provide the biochemical and structural basis of its mechanism using co-crystal structure of Pv cFRS with BRD1389.