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Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis

DOI: 10.1016/j.str.2017.07.015 DOI Help

Authors: Vitul Jain (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Manickam Yogavel (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Haruhisa Kikuchi (Tohoku University) , Yoshiteru Oshima (Tohoku University) , Norimitsu Hariguchi (Otsuka Pharmaceutical Co., Ltd) , Makoto Matsumoto (Otsuka Pharmaceutical Co., Ltd) , Preeti Goel (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Bastien Touquet (Institute for Advanced Biosciences (IAB), CNRS UMR5309, Grenoble Alpes University) , Rajiv S. Jumani (University of Vermont College of Medicine) , Fabienne Tacchini-cottier (University of Lausanne) , Karl Harlos (Wellcome Trust Centre for Human Genetics, University of Oxford) , Christopher D. Huston (University of Vermont College of Medicine) , Mohamed-ali Hakimi (Grenoble Alpes University) , Amit Sharma (International Centre for Genetic Engineering and Biotechnology (ICGEB))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure

State: Published (Approved)
Published: August 2017
Diamond Proposal Number(s): 14744

Abstract: Developing anti-parasitic lead compounds that act on key vulnerabilities are necessary for new anti-infectives. Malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis and coccidiosis together kill >500,000 humans annually. Their causative parasites Plasmodium, Leishmania, Toxoplasma, Cryptosporidium and Eimeria display high conservation in many housekeeping genes, suggesting that these parasites can be attacked by targeting invariant essential proteins. Here, we describe selective and potent inhibition of prolyl-tRNA synthetases (PRSs) from the above parasites using a series of quinazolinone-scaffold compounds. Our PRS-drug co-crystal structures reveal remarkable active site plasticity that accommodates diversely substituted compounds, an enzymatic feature that can be leveraged for refining drug-like properties of quinazolinones on a per parasite basis. A compound we termed In-5 exhibited a unique double conformation, enhanced drug-like properties, and cleared malaria in mice. It thus represents a new lead for optimization. Collectively, our data offer insights into the structure-guided optimization of quinazolinone-based compounds for drug development against multiple human eukaryotic pathogens.

Journal Keywords: malaria; leishmaniasis; toxoplasmosis; cryptosporidiosis; coccidiosis; drug discovery; prolyl-tRNA synthetase; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I04-Macromolecular Crystallography