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

Details

Serval ID
serval:BIB_EAF4765A995D
Type
Article: article from journal or magazin.
Collection
Publications
Title
Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis.
Journal
Structure
Author(s)
Jain V., Yogavel M., Kikuchi H., Oshima Y., Hariguchi N., Matsumoto M., Goel P., Touquet B., Jumani R.S., Tacchini-Cottier F., Harlos K., Huston C.D., Hakimi M.A., Sharma A.
ISSN
1878-4186 (Electronic)
ISSN-L
0969-2126
Publication state
Published
Issued date
03/10/2017
Peer-reviewed
Oui
Volume
25
Number
10
Pages
1495-1505.e6
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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.

Keywords
Amino Acyl-tRNA Synthetases/antagonists & inhibitors, Amino Acyl-tRNA Synthetases/chemistry, Animals, Catalytic Domain/drug effects, Coccidiosis/drug therapy, Cryptosporidiosis/drug therapy, Drug Discovery, Enzyme Inhibitors/administration & dosage, Enzyme Inhibitors/chemistry, Enzyme Inhibitors/pharmacology, Humans, Leishmaniasis/drug therapy, Malaria/drug therapy, Mice, Models, Molecular, Protozoan Infections/drug therapy, Protozoan Proteins/antagonists & inhibitors, Protozoan Proteins/chemistry, Quinazolinones/administration & dosage, Quinazolinones/chemistry, Quinazolinones/pharmacology, Structure-Activity Relationship, Toxoplasmosis/drug therapy, X-ray crystallography, coccidiosis, cryptosporidiosis, drug discovery, leishmaniasis, malaria, prolyl-tRNA synthetase, toxoplasmosis
Pubmed
Web of science
Create date
23/10/2017 10:15
Last modification date
20/08/2019 17:13
Usage data