1. Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy.
- Author
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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, and Creek DJ
- Subjects
- Humans, Aminopeptidases metabolism, Aminopeptidases antagonists & inhibitors, Aminopeptidases chemistry, Antimalarials pharmacology, Antimalarials chemistry, Plasmodium falciparum enzymology, Plasmodium falciparum drug effects, Plasmodium vivax enzymology, Plasmodium vivax drug effects, Protozoan Proteins metabolism, Protozoan Proteins antagonists & inhibitors, Protozoan Proteins chemistry, Proteomics methods
- 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 ( Pf A-M1) and Plasmodium vivax ( Pv A-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 Pf A-M1 in parasites, with limited proteolysis also enabling estimation of the binding site on Pf A-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 Pf A-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., Competing Interests: CG, MC, GS, RE, TM, CW, ND, NV, CM, NC, SD, SW, SD, VA, TD, PS, SM, DC No competing interests declared, (© 2024, Giannangelo, Challis et al.)
- Published
- 2024
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