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Publication Abstract from PubMed

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.

Toolkit of Approaches To Support Target-Focused Drug Discovery for Plasmodium falciparum Lysyl tRNA Synthetase.,Milne R, Wiedemar N, Corpas-Lopez V, Moynihan E, Wall RJ, Dawson A, Robinson DA, Shepherd SM, Smith RJ, Hallyburton I, Post JM, Dowers K, Torrie LS, Gilbert IH, Baragana B, Patterson S, Wyllie S ACS Infect Dis. 2022 Aug 29. doi: 10.1021/acsinfecdis.2c00364. PMID:36037410^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.