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- Title
Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy.
- Authors
Giannangelo, Carlo; Challis, Matthew P.; Siddiqui, Ghizal; Edgar, Rebecca; Malcolm, Tess R.; Webb, Chaille T.; Drinkwater, Nyssa; Vinh, Natalie; Macraild, Christopher; Counihan, Natalie; Duffy, Sandra; Wittlin, Sergio; Devine, Shane M.; Avery, Vicky M.; De Koning-Ward, Tania; Scammells, Peter; McGowan, Sheena; Creek, Darren J.
- 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.
- Subjects
PLASMODIUM; PLASMODIUM vivax; X-ray crystallography; PLASMODIUM falciparum; CYTOTOXINS
- Publication
eLife, 2024, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.92990