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

Vitul Jain, Manickam Yogavel, Haruhisa Kikuchi, Yoshiteru Oshima, Norimitsu Hariguchi, Makoto Matsumoto, Preeti Goel, Bastien Touquet, Rajiv S. Jumani, Fabienne Tacchini-Cottier, Karl Harlos, Christopher D. Huston, Mohamed Ali Hakimi, Amit Sharma

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

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. Synthesis and enzyme inhibition in multiple parasites, described by Jain et al., provides a new facet to quinazolinone-based inhibitors (QBIs). Multi-parasite drugging studies, coupled with structures of protein-drug complexes, reveal structural basis of QBI action. Structure-guided optimization and mice model studies reveal a top hit compound.

Original languageEnglish
Pages (from-to)1495-1505.e6
JournalStructure
Volume25
Issue number10
DOIs
Publication statusPublished - 2017 Oct 3

Keywords

  • X-ray crystallography
  • coccidiosis
  • cryptosporidiosis
  • drug discovery
  • leishmaniasis
  • malaria
  • prolyl-tRNA synthetase
  • toxoplasmosis

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Fingerprint

Dive into the research topics of 'Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis'. Together they form a unique fingerprint.

Cite this