ArticleProceedings of the National Academy of Sciences of the United States of America2012
Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
58 citing papers in PubMed, 1 synthesis or guideline pooled it, 105 citations in OpenAlex.
- Ubiquitin-proteasome system inFrontiers in medicine · 2024Pooled it
- The long and winding road: On the endoplasmic reticulum of Plasmodium and implications for pathogenesis.PLoS pathogens · 2026Review
- Inhibition of Histone Deacetylases Induces Cancer Cell Apoptosis Through the PERK Pathway of ER Stress Response.Journal of cellular and molecular medicine · 2025Article
- Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity.PLoS genetics · 2025Article
- A chaperonin complex regulates organelle proteostasis in malaria parasites.PLoS pathogens · 2025Article
- Unraveling the Role of Proteinopathies in Parasitic Infections.Biomedicines · 2025Review
- Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle.International journal of molecular sciences · 2024Review
- Signal Peptide Peptidase and PI4Kβ1/2 play opposite roles in plant ER stress response and immunity.Stress biology · 2024Article
- High Target Homology Does Not Guarantee Inhibition: Aminothiazoles Emerge as Inhibitors ofACS infectious diseases · 2024Article
- Chemo-proteomics in antimalarial target identification and engagement.Medicinal research reviews · 2023Review
- Knock-sideways by inducible ER retrieval enables a unique approach for studyingProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Inhibition of signal peptidase complex expression affects the development and survival ofFrontiers in cellular and infection microbiology · 2023Article
- Therapeutic Potential of Targeting Regulated Intramembrane Proteolysis Mechanisms of Voltage-Gated Ion Channel Subunits and Cell Adhesion Molecules.Pharmacological reviews · 2022Review
- Signal peptide peptidase: a potential therapeutic target for parasitic and viral infections.Expert opinion on therapeutic targets · 2022Review
- The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy.Frontiers in cellular and infection microbiology · 2022Review
- A redox-active crosslinker reveals an essential and inhibitable oxidative folding network in the endoplasmic reticulum of malaria parasites.PLoS pathogens · 2021Article
- Endoplasmic Reticulum Stress, a Target for Drug Design and Drug Resistance in Parasitosis.Frontiers in microbiology · 2021Review
- Yeast-based reporter assay system for identifying the requirements of intramembrane proteolysis by signal peptide peptidase of Arabidopsis thaliana.FEBS open bio · 2020Article
- Directing traffic: Chaperone-mediated protein transport in malaria parasites.Cellular microbiology · 2020Review
- Malaria parasite plasmepsins: More than just plain old degradative pepsins.The Journal of biological chemistry · 2020Review
Corrections and comments
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.