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

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Abstract

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
Volume8
Issue number9
Early online date29 Aug 2022
DOIs
Publication statusPublished - 9 Sep 2022

Keywords

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

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