Plasmodium falciparum endoplasmic reticulum protein transport system

The Plasmodium falciparum endoplasmic reticulum (ER) protein transport system is a specialized multi-protein machinery responsible for the translocation and processing of proteins destined for the parasite's organelles or export into the host erythrocyte [8, 13]. A central component of this system is the Sec61-Plasmepsin V translocon complex, which facilitates the co-translational entry of proteins into the ER lumen [8, 30]. Within this complex, the aspartyl protease Plasmepsin V (PMV) acts as a critical gatekeeper by recognizing and cleaving the Plasmodium export element (PEXEL) motif, a step essential for the export of approximately 10% of the parasite's proteome [20, 25]. These exported proteins are vital for remodeling the host red blood cell, establishing nutrient uptake channels, and evading the host immune system through the display of virulence factors like PfEMP1 [11, 21]. Because the system is essential for both asexual replication and the development of sexual stages (gametocytes), it represents a high-value target for antimalarial drug discovery [22, 23]. Small molecule inhibitors targeting Plasmepsin V, such as the WEHI series, have demonstrated potent antimalarial activity by blocking protein export and arresting parasite growth [20, 30]. However, achieving selectivity over human ER transport machinery and related proteases remains a significant therapeutic challenge [19, 29].

Other names

ER protein transport machineryER translocon complexSec61-Plasmepsin V complexER export systemPlasmodium falciparum ER transloconPfPMV-Sec61 complex

Inhibition of Plasmepsin V-mediated PEXEL cleavage, blockade of Sec61-mediated protein translocation, and inhibition of ER-to-Golgi vesicular trafficking.