Targeting Plasmepsins: Mechanism of Action and Inhibition Strategies

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Malaria is an infectious disease caused by the protozoan parasite, Plasmodium falciparum. The parasite relies on two crucial aspartic proteases, PMIX and PMX which are essential in red blood cell invasion and egress. For its survival, the parasite causes degradation of haemoglobin into amino acids which can be represented by the catalytic mechanism shown above.

Hydroxyethylamine (HEA) scaffolds have been shown to inhibit plasmepsins, preventing the parasite’s egress from host red blood cells. The HEA scaffolds mimic the tetrahedral intermediate by forming irreversible binding interactions, thereby blocking enzymatic activity and disrupting the parasites life cycle.

M. Lisauskaitė, G. L. Nixon, C. M. Woodley, N. G. Berry, A. Coninckx, L. C. Qie, S. C. Leung, D. Taramelli, N. Basilico, S. Parapini, S. A. Ward, O. Vadas, D. Soldati-Favre, W. D. Hong and P. M. O’Neill, RSC Chemical Biology, 2024, 5, 19–29.

Gupta, R. S. Yedidi, S. Varghese, L. C. Kovari and P. M. Woster, Journal of Medicinal Chemistry, 2010, 53, 4234–4247.