ArticleProceedings of the National Academy of Sciences of the United States of America2013
Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 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.
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Who cites it
67 citing papers in PubMed, 1 synthesis or guideline pooled it, 126 citations in OpenAlex.
- A resource for integrated genomic analysis of the human liver.Scientific reports · 2022Pooled it
- Review
- The impact of ERAP1 inhibition on metabolite homeostasis of melanoma cells.Scientific reports · 2026Article
- Discovery of New Nanomolar Selective IRAP Inhibitors.Journal of medicinal chemistry · 2025Article
- HLA-B27 and spondyloarthritis: at the crossroads of innate and adaptive immunity.Nature reviews. Rheumatology · 2025Review
- Unveiling the impact of ERAP1 and ERAP2 on migration, angiogenesis and ER stress response.Frontiers in cell and developmental biology · 2025Review
- Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.ACS medicinal chemistry letters · 2024Article
- Unveiling the therapeutic potential ofHeliyon · 2024Article
- ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights.Journal of medicinal chemistry · 2024Review
- Inhibition of Insulin-Regulated Aminopeptidase by Imidazo [1,5-α]pyridines-Synthesis and Evaluation.International journal of molecular sciences · 2024Article
- Polymorphic positions 349 and 725 of the autoimmunity-protective allotype 10 of ER aminopeptidase 1 are key in determining its unique enzymatic properties.Frontiers in immunology · 2024Article
- Paradoxical Effects of Endoplasmic Reticulum Aminopeptidase 1 Deficiency on HLA-B27 and Its Role as an Epistatic Modifier in Experimental Spondyloarthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2023Article
- Phosphinic Peptides as Tool Compounds for the Study of Pharmacologically Relevant Zn-Metalloproteases.ACS pharmacology & translational science · 2022Review
- Discovery of the First Selective Nanomolar Inhibitors of ERAP2 by Kinetic Target-Guided Synthesis.Angewandte Chemie (International ed. in English) · 2022Article
- Phenylsulfamoyl Benzoic Acid Inhibitor of ERAP2 with a Novel Mode of Inhibition.ACS chemical biology · 2022Article
- Conformational remodeling enhances activity of lanthipeptide zinc-metallopeptidases.Nature chemical biology · 2022Article
- Practical Synthesis of Phosphinic Dipeptides by Tandem Esterification of Aminophosphinic and Acrylic Acids under Silylating Conditions.Molecules (Basel, Switzerland) · 2022Article
- Inhibitor-Dependent Usage of the S1' Specificity Pocket of ER Aminopeptidase 2.ACS medicinal chemistry letters · 2022Article
- Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation.Frontiers in immunology · 2022Article
- Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism.Nature communications · 2021Article
7 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
Intracellular aminopeptidases endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), and as well as insulin-regulated aminopeptidase (IRAP) process antigenic epitope precursors for loading onto MHC class I molecules and regulate the adaptive immune response. Their activity greatly affects the antigenic peptide repertoire presented to cytotoxic T lymphocytes and as a result can regulate cytotoxic cellular responses contributing to autoimmunity or immune evasion by viruses and cancer cells. Therefore, pharmacological regulation of their activity is a promising avenue for modulating the adaptive immune response with possible applications in controlling autoimmunity, in boosting immune responses to pathogens, and in cancer immunotherapy. In this study we exploited recent structural and biochemical analysis of ERAP1 and ERAP2 to design and develop phosphinic pseudopeptide transition state analogs that can inhibit this family of enzymes with nM affinity. X-ray crystallographic analysis of one such inhibitor in complex with ERAP2 validated our design, revealing a canonical mode of binding in the active site of the enzyme, and highlighted the importance of the S2' pocket for achieving inhibitor potency. Antigen processing and presentation assays in HeLa and murine colon carcinoma (CT26) cells showed that these inhibitors induce increased cell-surface antigen presentation of transfected and endogenous antigens and enhance cytotoxic T-cell responses, indicating that these enzymes primarily destroy epitopes in those systems. This class of inhibitors constitutes a promising tool for controlling the cellular adaptive immune response in humans by modulating the antigen processing and presentation pathway.
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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.