Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-12, Vol.109 (52), p.21486-21491
• Main Authors: Harbut, Michael B., Patel, Bhumit A., Yeung, Bryan K. S., McNamara, Case W., Bright, A. Taylor, Ballard, Jaime, Supek, Frantisek, Golde, Todd E., Winzeler, Elizabeth A., Diagana, Thierry T., Greenbaum, Doron C.
• Format: Article
• Language: English
• Subjects: Animals; Antimalarials; Antiparasitic Agents - chemistry; Antiparasitic Agents - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Base Sequence; Biodegradation; Biological Sciences; Cell lines; Computational Biology; Drug Design; Drug Resistance - drug effects; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum-Associated Degradation - drug effects; Eukaryotes; Genetic mutation; Hep G2 Cells; Humans; Inhibitory concentration 50; Life Cycle Stages - drug effects; Liver - drug effects; Liver - parasitology; Malaria; Molecular Sequence Data; Molecules; Parasites; Parasites - drug effects; Parasites - enzymology; Parasites - growth & development; Parasitic protozoa; Parasitism; Peptides; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Plasmodium falciparum - growth & development; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Proteasome Inhibitors - pharmacology; Proteins; Proteolysis - drug effects; Proteome - metabolism; Small Molecule Libraries - pharmacology; Toxoplasma - drug effects; Toxoplasma - enzymology; Toxoplasma - growth & development; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - enzymology; Trypanosoma cruzi - growth & development; Yeasts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1216016110

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.