Antimalarials: Review of Plasmepsins as Drug Targets and HIV Protease Inhibitors Interactions

Abstract

Malaria is a major global health concern with the majority of cases reported in regions of South-East Asia, Eastern Mediterranean, Western Pacific, the Americas, and Sub-Saharan Africa. The World Health Organization (WHO) estimated 216 million worldwide reported cases of malaria in 2016. It is an infection of the red blood cells by parasites of the genus Plasmodium with most severe and common forms caused by Plasmodium falciparum (P. falciparum or Pf) and Plasmodium vivax (P. vivax or Pv). Emerging parasite resistance to available antimalarial drugs poses great challenges to treatment. Currently, the first line of defense includes artemisinin combination therapies (ACTs), increasingly becoming less effective and challenging to combat new occurrences of drug-resistant parasites. This necessitates the urgent need for novel antimalarials that target new molecular pathways with a different mechanism of action from the traditional antimalarials. Several new inhibitors and potential drug targets of the parasites have been reported over the years. This review focuses on the malarial aspartic proteases known as plasmepsins (Plms) as novel drug targets and antimalarials targeting Plms. It further discusses inhibitors of hemoglobin-degrading plasmepsins Plm I, Plm II, Plm IV and Histo-aspartic proteases (HAP), as well as HIV protease inhibitors of plasmepsins.

Identification of Novel, Potent, and Selective Compounds against Malaria Using Glideosomal-Associated Protein 50 as a Drug Target

“…Inhibiting Plasmepsin, for example, results in inhibiiton of hemoglobin digestion. 64 Similarly, inhibiting cyclophilin, 65 glutaredoxins, 66 and other important proteins identified as probable binders of our lead compounds may cause metabolic stress, disrupt cellular homeostasis, and lead to cell death. 67 Bedaquiline is known to promote electroneutral uncoupling of respiration-driven ATP synthesis 68 in Mycobacterium tuberculosis when the mode of action of lead compounds in diseases other than malaria is examined.…”

“…It is well-known that the inhibition of these proteins causes cellular stress. Inhibiting Plasmepsin, for example, results in inhibiiton of hemoglobin digestion . Similarly, inhibiting cyclophilin, glutaredoxins, and other important proteins identified as probable binders of our lead compounds may cause metabolic stress, disrupt cellular homeostasis, and lead to cell death .…”

Plasmepsin Inhibitors in Antimalarial Drug Discovery: Medicinal Chemistry and Target Validation (2000 to Present)

“…A number of review and perspective articles have documented inhibitors of PMs reported in the literature over time. − However, these have been limited in scope (for instance, they either describe inhibitors of particular PMs such as hemoglobinases only or are limited to only nonpeptidomimetic inhibitors) with some being somewhat old. Therefore, we identified a need to comprehensively capture PM inhibitors reported in the literature in the past 2 decades without discrimination.…”