Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy
- Author(s)
- Giannangelo, C; Challis, MP; Siddiqui, G; Edgar, R; Malcolm, TR; Webb, CT; Drinkwater, N; Vinh, N; Macraild, C; Counihan, N; Duffy, S; Wittlin, S; Devine, SM; Avery, VM; de Koning-Ward, T; Scammells, P; McGowan, S; Creek, DJ;
- Journal Title
- Elife
- Abstract
- New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of Plasmodium M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant Plasmodium falciparum (PfA-M1) and Plasmodium vivax (PvA-M1) M1 metalloaminopeptidases, with selectivity over other Plasmodium and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity. Orthogonal label-free chemoproteomic methods based on thermal stability and limited proteolysis of whole parasite lysates revealed that MIPS2673 solely targets PfA-M1 in parasites, with limited proteolysis also enabling estimation of the binding site on PfA-M1 to within ~5 Å of that determined by X-ray crystallography. Finally, functional investigation by untargeted metabolomics demonstrated that MIPS2673 inhibits the key role of PfA-M1 in haemoglobin digestion. Combined, our unbiased multi-omic target deconvolution methods confirmed the on-target activity of MIPS2673, and validated selective inhibition of M1 alanyl metalloaminopeptidase as a promising antimalarial strategy.
- Publisher
- eLife
- Keywords
- *Antimalarials/pharmacology/chemistry; *Plasmodium falciparum/enzymology/drug effects; *Plasmodium vivax/enzymology/drug effects; Humans; *Protozoan Proteins/metabolism/antagonists & inhibitors/chemistry; *Proteomics/methods; Aminopeptidases/metabolism/antagonists & inhibitors/chemistry; P. falciparum; aminopeptidase; biochemistry; chemical biology; chemoproteomics; drug target; infectious disease; malaria; mass spectrometry; metabolomics; microbiology
- Research Division(s)
- Ubiquitin Signalling
- PubMed ID
- 38976500
- Publisher's Version
- https://doi.org/10.7554/eLife.92990
- Open Access at Publisher's Site
https://doi.org/10.7554/eLife.92990- Terms of Use/Rights Notice
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Creation Date: 2024-07-10 09:21:04
Last Modified: 2024-07-10 09:30:03