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Nat Commun DOI:10.1038/s41467-022-32630-4

Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance.

Publication TypeJournal Article
Year of Publication2022
AuthorsTye, MA, N Payne, C, Johansson, C, Singh, K, Santos, SA, Fagbami, L, Pant, A, Sylvester, K, Luth, MR, Marques, S, Whitman, M, Mota, MM, Winzeler, EA, Lukens, AK, Derbyshire, ER, Oppermann, U, Wirth, DF, Mazitschek, R
JournalNat Commun
Volume13
Issue1
Pages4976
Date Published2022 Aug 25
ISSN2041-1723
KeywordsAmino Acyl-tRNA Synthetases, Antimalarials, Humans, Piperidines, Plasmodium, Plasmodium falciparum, Quinazolinones, RNA, Transfer
Abstract

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.

DOI10.1038/s41467-022-32630-4
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/36008486?dopt=Abstract

Alternate JournalNat Commun
PubMed ID36008486
PubMed Central IDPMC9403976
Grant ListR01AI143723 / / U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) /
R01AI152533 / / U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) /
F31AI129412 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
T32GM008666 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
S10OD026929 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
OPP1054480 / / Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation) /
DGE1745303 / / National Science Foundation (NSF) /
A23900 / / Cancer Research UK (CRUK) /
20522 / ARC_ / Arthritis Research UK / United Kingdom