Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
Matthew P Challis
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
Ghizal Siddiqui
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
Rebecca Edgar
School of Medicine, Deakin University, Geelong, Australia; The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Australia
Tess R Malcolm
Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia; Centre to Impact AMR, Monash University, Clayton, Australia
Chaille T Webb
Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia; Centre to Impact AMR, Monash University, Clayton, Australia
Nyssa Drinkwater
Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia; Centre to Impact AMR, Monash University, Clayton, Australia
Natalie Vinh
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
Christopher Macraild
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
School of Medicine, Deakin University, Geelong, Australia; The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Australia
Sandra Duffy
Discovery Biology, Centre for Cellular Phenomics, Griffith University, Nathan, Australia
Sergio Wittlin
Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Australia
Vicky M Avery
Discovery Biology, Centre for Cellular Phenomics, Griffith University, Nathan, Australia; School of Environment and Science, Griffith University, Nathan, Australia
Tania De Koning-Ward
School of Medicine, Deakin University, Geelong, Australia; The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Australia
Peter Scammells
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia; Centre to Impact AMR, Monash University, Clayton, Australia
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.
