Toolkit of Approaches To Support Target-Focused Drug Discovery for Plasmodium falciparum Lysyl tRNA Synthetase.
ACS Infect Dis
; 8(9): 1962-1974, 2022 09 09.
Article
in En
| MEDLINE
| ID: mdl-36037410
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Lysine-tRNA Ligase
/
Malaria
/
Antimalarials
Limits:
Humans
Language:
En
Journal:
ACS Infect Dis
Year:
2022
Type:
Article
Affiliation country:
United kingdom