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Toolkit of Approaches To Support Target-Focused Drug Discovery for Plasmodium falciparum Lysyl tRNA Synthetase
[Image: see text] There is a pressing need for new medicines to prevent and treat malaria. Most antimalarial drug discovery is reliant upon phenotypic screening. However, with the development of improved target validation strategies, target-focused approaches are now being utilized. Here, we describ...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469095/ https://www.ncbi.nlm.nih.gov/pubmed/36037410 http://dx.doi.org/10.1021/acsinfecdis.2c00364 |
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author | Milne, Rachel Wiedemar, Natalie Corpas-Lopez, Victoriano Moynihan, Eoin Wall, Richard J. Dawson, Alice Robinson, David A. Shepherd, Sharon M. Smith, Robert J. Hallyburton, Irene Post, John M. Dowers, Karen Torrie, Leah S. Gilbert, Ian H. Baragaña, Beatriz Patterson, Stephen Wyllie, Susan |
author_facet | Milne, Rachel Wiedemar, Natalie Corpas-Lopez, Victoriano Moynihan, Eoin Wall, Richard J. Dawson, Alice Robinson, David A. Shepherd, Sharon M. Smith, Robert J. Hallyburton, Irene Post, John M. Dowers, Karen Torrie, Leah S. Gilbert, Ian H. Baragaña, Beatriz Patterson, Stephen Wyllie, Susan |
author_sort | Milne, Rachel |
collection | PubMed |
description | [Image: see text] There is a pressing need for new medicines to prevent and treat malaria. Most antimalarial drug discovery is reliant upon phenotypic screening. However, with the development of improved target validation strategies, target-focused approaches are now being utilized. Here, we describe the development of a toolkit to support the therapeutic exploitation of a promising target, lysyl tRNA synthetase (PfKRS). The toolkit includes resistant mutants to probe resistance mechanisms and on-target engagement for specific chemotypes; a hybrid KRS protein capable of producing crystals suitable for ligand soaking, thus providing high-resolution structural information to guide compound optimization; chemical probes to facilitate pulldown studies aimed at revealing the full range of specifically interacting proteins and thermal proteome profiling (TPP); as well as streamlined isothermal TPP methods to provide unbiased confirmation of on-target engagement within a biologically relevant milieu. This combination of tools and methodologies acts as a template for the development of future target-enabling packages. |
format | Online Article Text |
id | pubmed-9469095 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-94690952022-09-14 Toolkit of Approaches To Support Target-Focused Drug Discovery for Plasmodium falciparum Lysyl tRNA Synthetase Milne, Rachel Wiedemar, Natalie Corpas-Lopez, Victoriano Moynihan, Eoin Wall, Richard J. Dawson, Alice Robinson, David A. Shepherd, Sharon M. Smith, Robert J. Hallyburton, Irene Post, John M. Dowers, Karen Torrie, Leah S. Gilbert, Ian H. Baragaña, Beatriz Patterson, Stephen Wyllie, Susan ACS Infect Dis [Image: see text] There is a pressing need for new medicines to prevent and treat malaria. Most antimalarial drug discovery is reliant upon phenotypic screening. However, with the development of improved target validation strategies, target-focused approaches are now being utilized. Here, we describe the development of a toolkit to support the therapeutic exploitation of a promising target, lysyl tRNA synthetase (PfKRS). The toolkit includes resistant mutants to probe resistance mechanisms and on-target engagement for specific chemotypes; a hybrid KRS protein capable of producing crystals suitable for ligand soaking, thus providing high-resolution structural information to guide compound optimization; chemical probes to facilitate pulldown studies aimed at revealing the full range of specifically interacting proteins and thermal proteome profiling (TPP); as well as streamlined isothermal TPP methods to provide unbiased confirmation of on-target engagement within a biologically relevant milieu. This combination of tools and methodologies acts as a template for the development of future target-enabling packages. American Chemical Society 2022-08-29 2022-09-09 /pmc/articles/PMC9469095/ /pubmed/36037410 http://dx.doi.org/10.1021/acsinfecdis.2c00364 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Milne, Rachel Wiedemar, Natalie Corpas-Lopez, Victoriano Moynihan, Eoin Wall, Richard J. Dawson, Alice Robinson, David A. Shepherd, Sharon M. Smith, Robert J. Hallyburton, Irene Post, John M. Dowers, Karen Torrie, Leah S. Gilbert, Ian H. Baragaña, Beatriz Patterson, Stephen Wyllie, Susan Toolkit of Approaches To Support Target-Focused Drug Discovery for Plasmodium falciparum Lysyl tRNA Synthetase |
title | Toolkit of Approaches To Support Target-Focused Drug
Discovery for Plasmodium falciparum Lysyl tRNA Synthetase |
title_full | Toolkit of Approaches To Support Target-Focused Drug
Discovery for Plasmodium falciparum Lysyl tRNA Synthetase |
title_fullStr | Toolkit of Approaches To Support Target-Focused Drug
Discovery for Plasmodium falciparum Lysyl tRNA Synthetase |
title_full_unstemmed | Toolkit of Approaches To Support Target-Focused Drug
Discovery for Plasmodium falciparum Lysyl tRNA Synthetase |
title_short | Toolkit of Approaches To Support Target-Focused Drug
Discovery for Plasmodium falciparum Lysyl tRNA Synthetase |
title_sort | toolkit of approaches to support target-focused drug
discovery for plasmodium falciparum lysyl trna synthetase |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469095/ https://www.ncbi.nlm.nih.gov/pubmed/36037410 http://dx.doi.org/10.1021/acsinfecdis.2c00364 |
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