{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:10:16Z","timestamp":1791299416411,"version":"4.1.0"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"52","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,12,26]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    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\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    . By using a variety of methodologies, we validate that SPP inhibitors target\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    SPP in parasites, disrupt the protein\u2019s 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1216016110","type":"journal-article","created":{"date-parts":[[2012,12,11]],"date-time":"2012-12-11T21:28:16Z","timestamp":1355261296000},"page":"21486-21491","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":97,"title":["Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design"],"prefix":"10.1073","volume":"109","author":[{"given":"Michael B.","family":"Harbut","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhumit A.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan K. 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