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Inhibition of Plasmodium falciparum phenylalanine tRNA synthetase provides opportunity for antimalarial drug development

DOI: 10.1016/j.str.2022.03.017 DOI Help

Authors: Manmohan Sharma (International Centre for Genetic Engineering and Biotechnology (ICGEB); Jamia Hamdard) , Nachiappan Mutharasappan (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Yogavel Manickam (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Karl Harlos (University of Oxford) , Bruno Melillo (Broad Institute of Harvard and MIT; The Scripps Research Institute) , Eamon Comer (Broad Institute of Harvard and MIT) , Heena Tabassum (ICMR) , Suhel Parvez (Jamia Hamdard) , Stuart L. Schreiber (Broad Institute of Harvard and MIT; Harvard University) , Amit Sharma (International Centre for Genetic Engineering and Biotechnology (ICGEB); National Institute of Malarial Research (NIMR))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure , VOL 66

State: Published (Approved)
Published: April 2022
Diamond Proposal Number(s): 19946

Abstract: Bicyclic azetidine compounds possess antimalarial activity via targeting of the cytoplasmic Plasmodium falciparum (Pf) protein translation enzyme phenylalanine-tRNA synthetase (cFRS). These drugs kill parasites both in vitro and in vivo, including the blood, liver, and transmission developmental stages. Here we present the co-crystal structure of PfcFRS with a potent inhibitor, the bicyclic azetidine BRD7929. Our studies reveal high-affinity binding of BRD7929 with PfcFRS along with exquisite specificity compared with the human enzyme, leading in turn to potent and selective inhibition of the parasite enzyme. Our co-crystal structure shows that BRD7929 binds in the active site in the α subunit of PfcFRS, where it occupies the amino acid site, an auxiliary site, and partially the ATP site. This structural snapshot of inhibitor-bound PfcFRS thus provides a platform for the structure-guided optimization of novel antimalarial compounds.

Journal Keywords: BRD7929; co-crystal structure; drug selectivity

Diamond Keywords: Malaria

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Other Facilities: PROXIMA 1, PROXIMA 2 at SOLEIL

Added On: 27/04/2022 10:34

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)