Malaria parasite plasmepsins: More than just plain old degradative pepsins

Abstract

Plasmepsins are a group of diverse aspartic proteases in the malaria parasite Plasmodium. Their functions are strikingly multifaceted, ranging from hemoglobin degradation to secretory organelle protein processing for egress, invasion, and effector export. Some, particularly the digestive vacuole plasmepsins, have been extensively characterized, whereas others, such as the transmission-stage plasmepsins, are minimally understood. Some (e.g. plasmepsin V) have exquisite cleavage sequence specificity; others are fairly promiscuous. Some have canonical pepsin-like aspartic protease features, whereas others have unusual attributes, including the nepenthesin loop of plasmepsin V and a histidine in place of a catalytic aspartate in plasmepsin III. We have learned much about the functioning of these enzymes, but more remains to be discovered about their cellular roles and even their mechanisms of action. Their importance in many key aspects of parasite biology makes them intriguing targets for antimalarial chemotherapy. Further consideration of their characteristics suggests that some are more viable drug targets than others. Indeed, inhibitors of invasion and egress offer hope for a desperately needed new drug to combat this nefarious organism.

Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay

“…The minimum value was 7 while the highest value was 33. The average SEI value was 12, well within the lower limit threshold for SEI (15) defined as a good starting point by Kumar et al 24 . Abiraterone, a hydrophobic compound with a cLogP of 5.3 and PSA of 33 Å 2 had the highest SEI value.…”

Protease Inhibition—An Established Strategy to Combat Infectious Diseases

“…The subsequent development into six evolutionary subgroups (ASP clades A-F) is associated with various functions important for the parasitic way of life and the complicated course of apicomplexan lifecycles [34,35]. The P. falciparum genome encodes ten related ASPs, collectively referred to as plasmepsins (abbreviated as PfPMI-X), with plasmepsin III being tagged as a histo-aspartyl protease (HAP) [36]. Plasmepsins have been considered potential targets of antimalarial drugs after discovering the inhibitory effects of HIV-PIs on malaria [37].…”

“…Therefore, PfPMI, PfPMII, PfPMIV and HAP, located in the digestive vacuole of merozoites, were initially considered to be the enzyme targets of HIV-PIs. However, this was later refuted with reference to considerable functional redundancy of the P. falciparum vacuolar digestive system, where plasmepsins and cysteine hemoglobinases (falcipains) act synergistically, greatly reducing the effects of targeted inhibition of digestive plasmepsins [36]. PfPMVI, PfPMVII and PfPMVIII are three plasmepsin isoenzymes that are not produced by the blood stages of P. falciparum and are important for the development of malaria in mosquito vectors.…”

Crossing the Vacuolar Rubicon: Structural Insights into Effector Protein Trafficking in Apicomplexan Parasites

“…Microorganisms 2020, 8, x FOR PEER REVIEW 14 of 25 pepsin-like aspartic proteases in the malaria parasite. Ten plasmepsins have been identified; they are involved in various aspects of parasitic life, such as hemoglobin catabolism (PlmI-IV), egress and invasion (PlmIX and X), and effector export (PlmV) [94]. The crystal structures of P. vivax PlmV bound to potent synthetic inhibitors have revealed a plant-like fold and a malaria-specific insertion motif important for the cleavage of exported effectors [95] (Figure 9, Figure S6).…”