Early secretory and endoplasmic reticulum (ER)-localized proteins that are 
terminally misfolded or misassembled are degraded by a ubiquitin- and 
proteasome-mediated process known as ER-associated degradation (ERAD). Protozoan 
pathogens, including the causative agents of malaria, toxoplasmosis, 
trypanosomiasis, and leishmaniasis, contain a minimal ERAD network relative to 
higher eukaryotic cells, and, because of this, we observe that the malaria 
parasite Plasmodium falciparum is highly sensitive to the inhibition of 
components of this protein quality control system. Inhibitors that specifically 
target a putative protease component of ERAD, signal peptide peptidase (SPP), 
have high selectivity and potency for P. falciparum. By using a variety of 
methodologies, we validate that SPP inhibitors target P. falciparum SPP in 
parasites, disrupt the protein's ability to facilitate degradation of unstable 
proteins, and inhibit its proteolytic activity. These compounds also show low 
nanomolar activity against liver-stage malaria parasites and are also equipotent 
against a panel of pathogenic protozoan parasites. Collectively, these data 
suggest ER quality control as a vulnerability of protozoan parasites, and that 
SPP inhibition may represent a suitable transmission blocking antimalarial 
strategy and potential pan-protozoan drug target.