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

Manmohan Sharma, Nipun Malhotra, Manickam Yogavel, Karl Harlos, Bruno Melillo, Eamon Comer, Arthur Gonse, Suhel Parvez, Branko Mitasev, Francis G. Fang, Stuart L. Schreiber and Amit Sharma ()
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Manmohan Sharma: International Centre for Genetic Engineering and Biotechnology
Nipun Malhotra: International Centre for Genetic Engineering and Biotechnology
Manickam Yogavel: International Centre for Genetic Engineering and Biotechnology
Karl Harlos: University of Oxford
Bruno Melillo: Broad Institute of Harvard and MIT
Eamon Comer: Broad Institute of Harvard and MIT
Arthur Gonse: Broad Institute of Harvard and MIT
Suhel Parvez: Jamia Hamdard
Branko Mitasev: Eisai Inc.
Francis G. Fang: Eisai Inc.
Stuart L. Schreiber: Broad Institute of Harvard and MIT
Amit Sharma: International Centre for Genetic Engineering and Biotechnology

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract 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 PvcFRS-BRD1389 complex shows that the bicyclic azetidine ligand binds to two distinct sub-sites within the PvcFRS 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.

Date: 2021
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DOI: 10.1038/s41467-020-20478-5

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