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

Détails

ID Serval
serval:BIB_EAF4765A995D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis.
Périodique
Structure
Auteur(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
Statut éditorial
Publié
Date de publication
03/10/2017
Peer-reviewed
Oui
Volume
25
Numéro
10
Pages
1495-1505.e6
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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.

Mots-clé
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
Création de la notice
23/10/2017 10:15
Dernière modification de la notice
20/08/2019 17:13
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