Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy

Carlo Giannangelo, Matthew P. Challis, Ghizal Siddiqui, Rebecca Edgar, Tess R. Malcolm, Chaille T. Webb, Nyssa Drinkwater, Natalie Vinh, Christopher Macraild, Natalie Counihan, Sandra Duffy, Sergio Wittlin, Shane M. Devine, Vicky M. Avery, Tania De Koning-Ward, Peter Scammells, Sheena McGowan, Darren J. Creek

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article numberRP92990
Number of pages32
JournaleLife
Volume13
DOIs
Publication statusPublished - 8 Jul 2024

Keywords

  • aminopeptidase
  • biochemistry
  • chemical biology
  • chemoproteomics
  • drug target
  • infectious disease
  • malaria
  • mass spectrometry
  • metabolomics
  • microbiology
  • P. falciparum

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