Conformational ensemble of the TNF-derived peptide solnatide in solution.
Comput Struct Biotechnol J
; 20: 2082-2090, 2022.
Article
in En
| MEDLINE
| ID: mdl-35601958
ABSTRACT
Tumor necrosis factor (TNF) is a homotrimer that has two spatially distinct binding regions, three lectin-like domains (LLD) at the TIP of the protein and three basolaterally located receptor-binding sites, the latter of which are responsible for the inflammatory and cell death-inducing properties of the cytokine. Solnatide (a.k.a. TIP peptide, AP301) is a 17-mer cyclic peptide that mimics the LLD of human TNF which activates the amiloride-sensitive epithelial sodium channel (ENaC) and, as such, recapitulates the capacity of TNF to enhance alveolar fluid clearance, as demonstrated in numerous preclinical studies. TNF and solnatide interact with glycoproteins and these interactions are necessary for their trypanolytic and ENaC-activating activities. In view of the crucial role of ENaC in lung liquid clearance, solnatide is currently being evaluated as a novel therapeutic agent to treat pulmonary edema in patients with moderate-to-severe acute respiratory distress syndrome (ARDS), as well as severe COVID-19 patients with ARDS. To facilitate the description of the functional properties of solnatide in detail, as well as to further target-docking studies, we have analyzed its folding properties by NMR. In solution, solnatide populates a set of conformations characterized by a small hydrophobic core and two electrostatically charged poles. Using the structural information determined here and also that available for the ENaC protein, we propose a model to describe solnatide interaction with the C-terminal domain of the ENaCα subunit. This model may serve to guide future experiments to validate specific interactions with ENaCα and the design of new solnatide analogs with unexplored functionalities.
AP301 peptide; ARDS, Acute Respiratory Distress Syndrome; AlphaFold applications; Alveolar fluid clearance; Amiloride-sensitive epithelial sodium channel; Amphipathic helix; ENaC; ENaC, Amiloride-sensitive Epithelial Sodium/Channel; HPLC, High Performance Liquid Chromatography; HSQC, Heteronuclear Single Quantum Coherence; LLD, Lectin-Like Domains; MARCKS, Myristoylated Alanine-Rich C Kinase Substrate; NMR, Nuclear Magnetic Resonance; NOESY, Nuclear Overhauser Effect Spectroscopy; PIP2, Phosphatidylinositol Bisphosphate; Peptide NMR; Pulmonary edema; Solnatide structure; TIP peptide; TM, Transmembrane Regions; TNF, Tumor Necrosis Factor; TOCSY, Total Correlation Spectroscopy; Tumor necrosis factor
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
Language:
En
Journal:
Comput Struct Biotechnol J
Year:
2022
Type:
Article
Affiliation country:
Spain