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

Mark A. Tye, N. Connor Payne, Catrine Johansson, Kritika Singh, Sofia A. Santos, Lọla Fagbami, Akansha Pant, Kayla Sylvester, Madeline R. Luth, Sofia Marques, Malcolm Whitman, Maria M. Mota, Elizabeth A. Winzeler, Amanda K. Lukens, Emily R. Derbyshire, Udo Oppermann, Dyann F. Wirth and Ralph Mazitschek ()
Additional contact information
Mark A. Tye: Massachusetts General Hospital
N. Connor Payne: Massachusetts General Hospital
Catrine Johansson: University of Oxford
Kritika Singh: Massachusetts General Hospital
Sofia A. Santos: Massachusetts General Hospital
Lọla Fagbami: Massachusetts General Hospital
Akansha Pant: Harvard T.H. Chan School of Public Health
Kayla Sylvester: Duke University
Madeline R. Luth: University of California, San Diego
Sofia Marques: Universidade de Lisboa
Malcolm Whitman: Harvard School of Dental Medicine
Maria M. Mota: Universidade de Lisboa
Elizabeth A. Winzeler: University of California, San Diego
Amanda K. Lukens: Broad Institute of MIT and Harvard
Emily R. Derbyshire: Duke University
Udo Oppermann: University of Oxford
Dyann F. Wirth: Harvard T.H. Chan School of Public Health
Ralph Mazitschek: Massachusetts General Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-32630-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32630-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-32630-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().