ArticleMolecular pharmacology2013
Mechanism of action of novel lung edema therapeutic AP301 by activation of the epithelial sodium channel.
Article in Molecular pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
- Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial.Critical care (London, England) · 2017Trial
- Antimicrobial peptides in the era of resistance: integrating AI-driven design, host-microbe interactions, and nanotechnological delivery.Frontiers in microbiology · 2026Review
- The lectin-like domain of TNF reduces pneumonia-induced injury in the perfused human lung.JCI insight · 2025Article
- Automated patch-clamp recordings for detecting activators and inhibitors of the epithelial sodium channel (ENaC).Pflugers Archiv : European journal of physiology · 2025Article
- The small molecule activator S3969 stimulates the epithelial sodium channel by interacting with a specific binding pocket in the channel's β-subunit.The Journal of biological chemistry · 2024Article
- Proteolytic Activation of the Epithelial Sodium Channel (ENaC): Its Mechanisms and Implications.International journal of molecular sciences · 2023Review
- Cyclic Peptides in Pipeline: What Future for These Great Molecules?Pharmaceuticals (Basel, Switzerland) · 2023Review
- The Epithelial Sodium Channel-An Underestimated Drug Target.International journal of molecular sciences · 2023Review
- Conformational ensemble of the TNF-derived peptide solnatide in solution.Computational and structural biotechnology journal · 2022Article
- CRISPR/Cas9 Mediated Knock Down of δ-ENaC Blunted the TNF-Induced Activation of ENaC in A549 Cells.International journal of molecular sciences · 2021Article
- Dichotomous Role of Tumor Necrosis Factor in Pulmonary Barrier Function and Alveolar Fluid Clearance.Frontiers in physiology · 2021Review
- Recent advances in understanding acute respiratory distress syndrome.F1000Research · 2018Review
- Inhalation therapies in acute respiratory distress syndrome.Annals of translational medicine · 2017Review
- TNF Lectin-Like Domain Restores Epithelial Sodium Channel Function in Frameshift Mutants Associated with Pseudohypoaldosteronism Type 1B.Frontiers in immunology · 2017Article
- Restoration of Epithelial Sodium Channel Function by Synthetic Peptides in Pseudohypoaldosteronism Type 1B Mutants.Frontiers in pharmacology · 2017Article
- Epithelial Sodium Channels in Pulmonary Epithelial Progenitor and Stem Cells.International journal of biological sciences · 2016Review
- A potential role for interleukin-33 and γ-epithelium sodium channel in the pathogenesis of human malaria associated lung injury.Malaria journal · 2015Article
- Inhalation therapy with the synthetic TIP-like peptide AP318 attenuates pulmonary inflammation in a porcine sepsis model.BMC pulmonary medicine · 2015Article
- A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation.American journal of respiratory and critical care medicine · 2014Article
- TIP peptide inhalation in experimental acute lung injury: effect of repetitive dosage and different synthetic variants.BMC anesthesiology · 2014Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
AP301 [Cyclo(CGQRETPEGAEAKPWYC)], a cyclic peptide comprising the human tumor necrosis factor lectin-like domain (TIP domain) sequence, is currently being developed as a treatment for lung edema and has been shown to reduce extravascular lung water and improve lung function in mouse, rat, and pig models. The current paradigm for liquid homeostasis in the adult mammalian lung is that passive apical uptake of sodium via the amiloride-sensitive epithelial Na⁺ channel (ENaC) and nonselective cyclic-nucleotide-gated cation channels creates the major driving force for reabsorption of water through the alveolar epithelium in addition to other ion channels such as potassium and chloride channels. AP301 can increase amiloride-sensitive current in A549 cells as well as in freshly isolated type II alveolar epithelial cells from different species. ENaC is expressed endogenously in all of these cell types. Consequently, this study was undertaken to determine whether ENaC is the specific target of AP301. The effect of AP301 in A549 cells as well as in human embryonic kidney cells and Chinese hamster ovary cells heterologously expressing human ENaC subunits (α, β, γ, and δ) was measured in patch clamp experiments. The congener TIP peptide AP318 [Cyclo(4-aminobutanoic acid-GQRETPEGAEAKPWYD)] activated ENaC by increasing single-channel open probability. AP301 increased current in proteolytically activated (cleaved) but not near-silent (uncleaved) ENaC in a reversible manner. αβγ- or δβγ-ENaC coexpression was required for maximal activity. No increase in current was observed after deglycosylation of extracellular domains of ENaC. Thus, our data suggest that the specific interaction of AP301 with both endogenously and heterologously expressed ENaC requires precedent binding to glycosylated extracellular loop(s).
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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.