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

Detalhes bibliográficos
Autor(a) principal: Tye, Mark A.
Data de Publicação: 2022
Outros Autores: Payne, N. Connor, Johansson, Catrine, Singh, Kritika, Santos, Sofia A., Fagbami, Lọla, Pant, Akansha, Sylvester, Kayla, Luth, Madeline R., Marques, Sofia, Whitman, Malcolm, Mota, Maria M., Winzeler, Elizabeth A., Lukens, Amanda K., Derbyshire, Emily R., Oppermann, Udo, Wirth, Dyann F., Mazitschek, Ralph
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/54410
Resumo: © The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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spelling Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance© The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.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.This work was supported by NIH R01AI143723 (R.M. and D.F.W.), NIH R01AI152533 (M.R.L. and E.A.W.), 5F31AI129412 (L.F.), and the Bill & Melinda Gates Foundation (OPP1054480, E.A.W. and D.F.W.), LEAN program of the Leducq Foundation (U.O.), Arthritis Research UK 20522 (U.O.), Cancer Research UK A23900 (U.O.). N.C.P. was supported by a National Science Foundation Graduate Research Fellowship (DGE1745303). M.R.L. was supported in part by a Ruth L. Kirschstein Institutional National Research Award from the National Institute for General Medical Sciences (T32 GM008666). This publication includes data generated at the University of California, San Diego IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).Springer NatureRepositório da Universidade de LisboaTye, Mark A.Payne, N. ConnorJohansson, CatrineSingh, KritikaSantos, Sofia A.Fagbami, LọlaPant, AkanshaSylvester, KaylaLuth, Madeline R.Marques, SofiaWhitman, MalcolmMota, Maria M.Winzeler, Elizabeth A.Lukens, Amanda K.Derbyshire, Emily R.Oppermann, UdoWirth, Dyann F.Mazitschek, Ralph2022-09-09T13:20:03Z20222022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/54410engNat Commun. 2022 Aug 25;13(1):497610.1038/s41467-022-32630-42041-1723info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:00:43Zoai:repositorio.ul.pt:10451/54410Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:05:11.728656Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance
title Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance
spellingShingle Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance
Tye, Mark A.
title_short Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance
title_full Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance
title_fullStr Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance
title_full_unstemmed Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance
title_sort Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance
author Tye, Mark A.
author_facet Tye, Mark A.
Payne, N. Connor
Johansson, Catrine
Singh, Kritika
Santos, Sofia A.
Fagbami, Lọla
Pant, Akansha
Sylvester, Kayla
Luth, Madeline R.
Marques, Sofia
Whitman, Malcolm
Mota, Maria M.
Winzeler, Elizabeth A.
Lukens, Amanda K.
Derbyshire, Emily R.
Oppermann, Udo
Wirth, Dyann F.
Mazitschek, Ralph
author_role author
author2 Payne, N. Connor
Johansson, Catrine
Singh, Kritika
Santos, Sofia A.
Fagbami, Lọla
Pant, Akansha
Sylvester, Kayla
Luth, Madeline R.
Marques, Sofia
Whitman, Malcolm
Mota, Maria M.
Winzeler, Elizabeth A.
Lukens, Amanda K.
Derbyshire, Emily R.
Oppermann, Udo
Wirth, Dyann F.
Mazitschek, Ralph
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Tye, Mark A.
Payne, N. Connor
Johansson, Catrine
Singh, Kritika
Santos, Sofia A.
Fagbami, Lọla
Pant, Akansha
Sylvester, Kayla
Luth, Madeline R.
Marques, Sofia
Whitman, Malcolm
Mota, Maria M.
Winzeler, Elizabeth A.
Lukens, Amanda K.
Derbyshire, Emily R.
Oppermann, Udo
Wirth, Dyann F.
Mazitschek, Ralph
description © The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
publishDate 2022
dc.date.none.fl_str_mv 2022-09-09T13:20:03Z
2022
2022-01-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/54410
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dc.relation.none.fl_str_mv Nat Commun. 2022 Aug 25;13(1):4976
10.1038/s41467-022-32630-4
2041-1723
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