Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 08 2022
25 08 2022
Historique:
received:
11
12
2021
accepted:
10
08
2022
entrez:
25
8
2022
pubmed:
26
8
2022
medline:
30
8
2022
Statut:
epublish
Résumé
The development of next-generation antimalarials that are efficacious against the human liver and asexual blood stages is recognized as one of the world's most pressing public health challenges. In recent years, aminoacyl-tRNA synthetases, including prolyl-tRNA synthetase, have emerged as attractive targets for malaria chemotherapy. We describe the development of a single-step biochemical assay for Plasmodium and human prolyl-tRNA synthetases that overcomes critical limitations of existing technologies and enables quantitative inhibitor profiling with high sensitivity and flexibility. Supported by this assay platform and co-crystal structures of representative inhibitor-target complexes, we develop a set of high-affinity prolyl-tRNA synthetase inhibitors, including previously elusive aminoacyl-tRNA synthetase triple-site ligands that simultaneously engage all three substrate-binding pockets. Several compounds exhibit potent dual-stage activity against Plasmodium parasites and display good cellular host selectivity. Our data inform the inhibitor requirements to overcome existing resistance mechanisms and establish a path for rational development of prolyl-tRNA synthetase-targeted anti-malarial therapies.
Identifiants
pubmed: 36008486
doi: 10.1038/s41467-022-32630-4
pii: 10.1038/s41467-022-32630-4
pmc: PMC9403976
doi:
Substances chimiques
Antimalarials
0
Piperidines
0
Quinazolinones
0
RNA, Transfer
9014-25-9
Amino Acyl-tRNA Synthetases
EC 6.1.1.-
halofuginone
L31MM1385E
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4976Subventions
Organisme : Versus Arthritis
ID : 20522
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI152533
Pays : United States
Organisme : Arthritis Research UK
ID : 20522
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A23900
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : F31 AI129412
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008666
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI143723
Pays : United States
Organisme : NIH HHS
ID : S10 OD026929
Pays : United States
Informations de copyright
© 2022. The Author(s).
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