Affiliation:
1. Monash University
2. Deakin University
3. Griffith University
4. University of Basel
5. Walter and Eliza Hall Institute
6. Monash Institute of Pharmaceutical Sciences
Abstract
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 (Pv-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 strategies confirmed the on-target activity of MIPS2673, and validated selective inhibition of M1 alanyl metalloaminopeptidase as a promising multi-stage and cross-species antimalarial strategy.
Publisher
Research Square Platform LLC
Reference90 articles.
1. WHO (2022). World Malaria Report 2022. World Health Organisation.
2. Plasmodium vivax in the Era of the Shrinking P. falciparum Map;Price RN;Trends Parasitol.,2020
3. Phillips, M.A., Burrows, J.N., Manyando, C., van Huijsduijnen, R.H., Van Voorhis, W.C., and Wells, T.N.C. (2017). Malaria. Nat. Rev. Dis. Primers 3, 17050. https://doi.org/10.1038/nrdp.2017.50.
4. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study;Pluijm RW;Lancet Infect. Dis.,2019
5. Evidence of artemisinin-resistant malaria in Africa;Balikagala B;N. Engl. J. Med.,2021
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