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.