LAUSR

ABSTRACT Introduction Signal peptide peptidase (SPP) is a GxGD-type intramembrane-cleaving aspartyl protease responsible for clearing accumulating signal peptides in the endoplasmic reticulum. SPP is conserved among all kingdoms and is essential for maintaining cell homeostasis. Inhibition of SPP with selective inhibitors and the structurally similar HIV protease inhibitors results in signal peptide accumulation and subsequent cell death. Identification of SPP homologues in major human parasitic infections has opened a new therapeutic opportunity. Moreover, the essentiality of mammalian SPP-mediated viral protein processing during infection is emerging. Areas Covered This review introduces the discovery and biological function of human SPP enzymes and identify parasitic homologues as pharmacological targets of both SPP and HIV protease inhibitors. Later, the role of mammalian SPP during viral infection and how disruption of host SPP can be employed as a novel antiviral therapy are examined and discussed. Expert Opinion Parasitic and viral infections cause severe health and economic burden, exacerbated by the lack of new therapeutics in the pipeline. SPP has been shown to be essential for malaria parasite growth and encouraging evidence in other parasites demonstrates broad essentiality of these proteases as therapeutic targets. As drug resistant parasite and viruses emerge, SPP inhibition will provide a new generation of compounds to counter the growing threat of antimicrobial resistance.