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Toolkit of approaches to support target-focused drug discovery for Plasmodium falciparum lysyl tRNA synthetase

DOI: 10.1021/acsinfecdis.2c00364 DOI Help

Authors: Rachel Milne (University of Dundee) , Natalie Wiedemar (University of Dundee) , Victoriano Corpas-Lopez (University of Dundee) , Eoin Moynihan (University of Dundee) , Richard J. Wall (University of Dundee) , Alice Dawson (University of Dundee) , David A. Robinson (University of Dundee) , Sharon M. Shepherd (University of Dundee) , Robert J. Smith (University of Dundee) , Irene Hallyburton (University of Dundee) , John M. Post (University of Dundee) , Karen Dowers (University of Dundee) , Leah S. Torrie (University of Dundee) , Ian H. Gilbert (University of Dundee) , Beatriz BaragaƱa (University of Dundee) , Stephen Patterson (University of Dundee) , Susan Wyllie (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: August 2022
Diamond Proposal Number(s): 19844

Open Access Open Access

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.

Journal Keywords: Plasmodium lysyl tRNA synthetase; thermal proteome profiling (TPP); isothermal TPP; chemical pulldown; antimalarial drug discovery

Diamond Keywords: Malaria

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 31/08/2022 14:52

Documents:
acsinfecdis.2c00364.pdf

Discipline Tags:

Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)