Aminopeptidase Inhibition Strategies in Malaria Therapeutics

Malaria, caused by Plasmodium parasites, relies on the degradation of host haemoglobin to fuel growth within red blood cells. Aminopeptidases, key enzymes that cleave N-terminal amino acids from peptide fragments, are integral to this process. Two principal families, the M1 alanyl aminopeptidases and M17 leucyl aminopeptidases, coordinate successive steps in haemoglobin catabolism, generating free amino acids required for parasite protein synthesis and osmoregulation. Inhibiting these metalloaminopeptidases has emerged as a promising antimalarial strategy. Selective inhibitors can arrest parasite development by disrupting haemoglobin processing, triggering amino acid starvation, and sensitising parasites to existing therapies. Recent efforts have focused on refining inhibitor selectivity, optimising metal-binding groups, and exploring dual targeting of multiple aminopeptidases to overcome resistance and broaden species coverage. Structural insights from crystallography and chemoproteomic profiling have guided the design of compounds that engage key active-site residues while sparing host enzymes. These strategies hold potential for novel therapeutics that complement or replace current artemisinin-based treatments and address the global challenge of drug-resistant malaria.

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Aminopeptidase Inhibition Strategies in Malaria Therapeutics publication trend

The graph below shows the total number of articles in aminopeptidase inhibition strategies in malaria therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Aminopeptidase: Enzyme that cleaves amino acids sequentially from the N-terminus of peptide substrates.

Metalloaminopeptidase: Aminopeptidase requiring a metal ion, typically zinc, for catalytic activity.

PfA-M1 and PfA-M17: M1 and M17 family aminopeptidases expressed by Plasmodium falciparum, essential for haemoglobin catabolism.

Chemoproteomics: Technique combining chemical probes and proteomics to identify and validate protein targets of small molecules in complex biological systems.

References

1. Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy. eLife (2024).
2. On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity. mBio (2024).
3. Drug targeting of aminopeptidases: importance of deploying a right metal cofactor. Biophysical Reviews (2024).