ArticleProceedings of the National Academy of Sciences of the United States of America2021
Novel allosteric ligands of the angiotensin receptor AT1R as autoantibody blockers.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 25 citations in OpenAlex.
- Berberine Ameliorates Angiotensin II-Induced Endothelial Dysfunction by Blocking AT1R, Inhibiting PDE4b and Activating AKT/eNOS Pathway.Chinese journal of integrative medicine · 2026Article
- Microbial Metabolite 4EPS Inhibits AT1R to Reduce Blood Pressure and Aortic Aneurysm Outcome.Hypertension (Dallas, Tex. : 1979) · 2026Article
- The Concise Guide to PHARMACOLOGY 2025/26: G protein-coupled receptors.British journal of pharmacology · 2025Review
- Article
- Absence of Functional Autoantibodies Targeting Angiotensin II Receptor Type 1 and Endothelin-1 Type A Receptor in Circulation and Purified IgG From Patients With Systemic Sclerosis.Arthritis & rheumatology (Hoboken, N.J.) · 2025Article
- Reductions in angiotensin II type 2 receptor-mediated vasodilation contribute to increased angiotensin II vasoconstrictor sensitivity in women with preeclampsia history.Clinical science (London, England : 1979) · 2025Article
- How New Developments in Pharmacology Receptor Theory Are Changing (Our Understanding of) Hypertension Therapy.American journal of hypertension · 2024Review
- AT1-AA Is Produced in Offspring in Response to Placental Ischemia and Is Lowered by B-Cell Depletion Without Compromising Overall Offspring Health.Journal of the American Heart Association · 2024Article
- The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors.British journal of pharmacology · 2023Article
- Advances in the allostery of angiotensin II type 1 receptor.Cell & bioscience · 2023Review
- The role of immune cells and mediators in preeclampsia.Nature reviews. Nephrology · 2023Review
- Data-driven analysis and druggability assessment methods to accelerate the identification of novel cancer targets.Computational and structural biotechnology journal · 2023Review
- Unraveling the relationship between the renin-angiotensin system and endometrial cancer: a comprehensive review.Frontiers in oncology · 2023Review
- Aptamer-assisted two-point immobilized agonist-bound angiotensin II type 1 receptor for a second-site modulator discovery.iScience · 2022Article
- Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric modulation in angiotensin receptors: IUPHAR Review 34.British journal of pharmacology · 2022Review
- Non-HLA Antibodies in Hand Transplant Recipients Are Connected to Multiple Acute Rejection Episodes and Endothelial Activation.Journal of clinical medicine · 2022Article
- The relationship between chronic immune response and neurodegenerative damage in long COVID-19.Frontiers in immunology · 2022Review
- Identification of a Novel Delta Opioid Receptor Agonist Chemotype with Potential Negative Allosteric Modulator Capabilities.Molecules (Basel, Switzerland) · 2021Article
- Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
While orthosteric ligands of the angiotensin II (AngII) type 1 receptor (AT1R) are available for clinical and research applications, allosteric ligands are not known for this important G protein-coupled receptor (GPCR). Allosteric ligands are useful tools to modulate receptor pharmacology and subtype selectivity. Here, we report AT1R allosteric ligands for a potential application to block autoimmune antibodies. The epitope of autoantibodies for AT1R is outside the orthosteric pocket in the extracellular loop 2. A molecular dynamics simulation study of AT1R structure reveals the presence of a druggable allosteric pocket encompassing the autoantibody epitope. Small molecule binders were then identified for this pocket using structure-based high-throughput virtual screening. The top 18 hits obtained inhibited the binding of antibody to AT1R and modulated agonist-induced calcium response of AT1R. Two compounds out of 18 studied in detail exerted a negative allosteric modulator effect on the functions of the natural agonist AngII. They blocked antibody-enhanced calcium response and reactive oxygen species production in vascular smooth muscle cells as well as AngII-induced constriction of blood vessels, demonstrating their efficacy in vivo. Our study thus demonstrates the feasibility of discovering inhibitors of the disease-causing autoantibodies for GPCRs. Specifically, for AT1R, we anticipate development of more potent allosteric drug candidates for intervention in autoimmune maladies such as preeclampsia, bilateral adrenal hyperplasia, and the rejection of organ transplants.
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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.