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

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.

• Authors: 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
• Journal: Structure (London, England : 1993) (Structure) Vol. 25 Issue 10 Pg. 1495-1505.e6 (10 03 2017) ISSN: 1878-4186 [Electronic] United States
• PMID: 28867614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Protozoan Proteins
• Quinazolinones
• Amino Acyl-tRNA Synthetases
• prolyl T RNA synthetase

Topics

• Amino Acyl-tRNA Synthetases (antagonists & inhibitors, chemistry)
• Animals
• Catalytic Domain (drug effects)
• Coccidiosis (drug therapy)
• Cryptosporidiosis (drug therapy)
• Drug Discovery
• Enzyme Inhibitors (administration & dosage, chemistry, pharmacology)
• Humans
• Leishmaniasis (drug therapy)
• Malaria (drug therapy)
• Mice
• Models, Molecular
• Protozoan Infections (drug therapy)
• Protozoan Proteins (antagonists & inhibitors, chemistry)
• Quinazolinones (administration & dosage, chemistry, pharmacology)
• Structure-Activity Relationship
• Toxoplasmosis (drug therapy)