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

Autor: Tye MA; Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.; Harvard Graduate School of Arts and Sciences, Cambridge, MA, USA.; Harvard T.H. Chan School of Public Health, Boston, MA, USA., Payne NC; Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA., Johansson C; Botnar Research Centre, NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK.; Centre for Medicines Discovery, University of Oxford, Oxford, UK., Singh K; Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.; Department of Bioengineering, Northeastern University, Boston, MA, USA., Santos SA; Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA., Fagbami L; Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.; Harvard Graduate School of Arts and Sciences, Cambridge, MA, USA.; Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Pant A; Harvard T.H. Chan School of Public Health, Boston, MA, USA., Sylvester K; Department of Chemistry, Duke University, Durham, NC, USA., Luth MR; Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA., Marques S; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal., Whitman M; Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA., Mota MM; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal., Winzeler EA; Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA., Lukens AK; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Derbyshire ER; Department of Chemistry, Duke University, Durham, NC, USA., Oppermann U; Botnar Research Centre, NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK.; Centre for Medicines Discovery, University of Oxford, Oxford, UK., Wirth DF; Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Mazitschek R; Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. ralph@broadinstitute.org.; Harvard T.H. Chan School of Public Health, Boston, MA, USA. ralph@broadinstitute.org.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. ralph@broadinstitute.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Aug 25; Vol. 13 (1), pp. 4976. Date of Electronic Publication: 2022 Aug 25.
DOI: 10.1038/s41467-022-32630-4
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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