Conformational ensemble of the TNF-derived peptide solnatide in solution

• Type of Material: Article
• Authors: Pau Martin-Malpartida, The Barcelona Institute of Science and Technology; Silvia Arrastia-Casado, BCN Peptides SA Pol Ind Els Vinyets Els Fogars; Josep Farrera-Sinfreu, BCN Peptides SA Pol Ind Els Vinyets Els Fogars; Rudolf Lucas, Augusta University; Hendrick Fischer, APEPTICO Forschung und Entwicklung GmbH; Bernhard Fischer, APEPTICO Forschung und Entwicklung GmbH; Douglas Eaton, Emory University; Susan Tzotzos, APEPTICO Forschung und Entwicklung GmbH; Maria J Macias, The Barcelona Institute of Science and Technology
• Language: English
• Date: 2022-01-01
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Author(s)
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.csbj.2022.04.031
• Title of Journal or Parent Work: COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
• Volume: 20
• Start Page: 2082
• End Page: 2090
• Grant/Funding Information: The study was supported, in part, by the EU special H2020 program “Advancing knowledge for the clinical and public health response to the 2019-nCoV epidemic” (call ID: SC1-PHE-CORONAVIRUS-2020) under the grant number 101003595, and by the Austrian Research Promotion Agency (FFG), Grant No.880862. RL and DCE were supported by R01 grant HL138410 from the NIH/NHLBI, DCE is supported by U.S. NIH grant DK-110409. M.J.M. is an ICREA Program Investigator.
• Keywords: AlphaFold applications; Life Sciences & Biomedicine; AP301 peptide; Biochemistry & Molecular Biology; Amiloride-sensitive epithelial sodium; LECTIN-LIKE DOMAIN; Alveolar fluid clearance; Peptide NMR; Science & Technology; Solnatide structure; TUMOR-NECROSIS-FACTOR; PROTEIN STRUCTURES; ACTIVATION; FACTOR-ALPHA; EPITHELIAL SODIUM-CHANNEL; Amphipathic helix; RESOLUTION; Biotechnology & Applied Microbiology; Tumor necrosis factor; IDENTIFICATION; ENaC; channel; CRYSTALLOGRAPHY; Pulmonary edema; TIP peptide; SOMATOSTATIN ANALOGS
• Research Categories: Health Sciences, Medicine and Surgery

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.