Toolkit of Approaches To Support Target-Focused Drug Discovery for Plasmodium falciparum Lysyl tRNA Synthetase

Rachel Milne, Natalie Wiedemar, Victoriano Corpas Lopez, Eoin Moynihan, Richard J. Wall, Alice Dawson, David A. Robinson, Sharon M. Shepherd, Robert J. Smith, Irene Hallyburton, John M. Post, Karen Dowers, Leah S. Torrie, Ian H. Gilbert, Beatriz Baragaña, Stephen Patterson, Susan Wyllie (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1962-1974
Number of pages13
JournalACS Infectious Diseases
Issue number9
Early online date29 Aug 2022
Publication statusPublished - 9 Sept 2022


  • Plasmodium
  • lysyl tRNA synthetase
  • thermal proteome profiling (TPP)
  • isothermal TPP
  • chemical pulldown
  • anti-malarial drug discover
  • antimalarial drug discovery

ASJC Scopus subject areas

  • Infectious Diseases


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