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Although CFTR modulators have improved clinical outcomes, a subset of patients remains unresponsive to current therapies, highlighting the need for alternative strategies. The frog skin-derived antimicrobial peptide Esc(1\u201321) was recently identified as a CFTR potentiator, likely through direct interaction with the interface of the channel\u2019s cytosolic nucleotide-binding domains (NBDs); yet its molecular mechanism is poorly understood. Here, we engineered a cysteine-less CFTR scaffold by introducing cysteine pairs within or outside the predicted peptide-binding region and used molecular dynamics simulation to define the putative interaction site. Disulfide cross-linking assays performed in cells expressing these constructs validated the computational predictions and showed that the peptide selectively prevents cross-link formation only when cysteines are positioned at the NBD interface, thereby supporting a direct and specific interaction with CFTR. Importantly, confocal microscopy provided evidence for peptide intracellular internalization, together with colocalization with the ion channel, indicating that Esc(1\u201321) can access the cytosolic side of CFTR to enhance its activity. Overall, these findings (i) provide the first mechanistic insights into the interaction of Esc(1\u201321) with CFTR in a cellular context; (ii) identify the NBD1-NBD2 interface as a suitable target for peptide-based potentiators; and (iii) support the development of Esc(1\u201321) and its derivatives as novel multifunctional therapeutic candidates for CF treatment.<\/jats:p>","DOI":"10.1021\/acsomega.6c03409","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:02:02Z","timestamp":1786975322000},"page":"51094-51105","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic Insights\ninto CFTR Potentiation by the\nAntimicrobial Peptide Esc(1\u201321): Direct Interaction with the\nNBD1-NBD2 Interface"],"prefix":"10.1021","volume":"11","author":[{"given":"Debora","family":"Baroni","sequence":"first","affiliation":[{"name":"Consiglio Nazionale Delle Ricerche, CNR , , via De Marini 6 , ,","place":["Genova, Italy, 16149"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loretta","family":"Ferrera","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Giannina Gaslini , , via Gerolamo Gaslini 5 , ,","place":["Genova, Italy, 16147"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Passalacqua","sequence":"additional","affiliation":[{"name":"University of Genova , , Viale Benedetto XV 1 , ,","place":["Genova, Italy, 16132"]},{"name":"Inter-University Centre for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R) , ,","place":["Torino, Italy, 10125"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Cappella","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , Piazzale A. Moro 5 , ,","place":["Roma, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Astigiano","sequence":"additional","affiliation":[{"name":"University of Genova , , Viale Benedetto XV 1 , ,","place":["Genova, Italy, 16132"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2028-2087","authenticated-orcid":true,"given":"Y. Peter","family":"Di","sequence":"additional","affiliation":[{"name":"Florida International University , , 11350 SW Village Pkwy , , ,","place":["Port St. Lucie, Florida, United States, 34987"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2398-1254","authenticated-orcid":true,"given":"Mattia","family":"Mori","sequence":"additional","affiliation":[{"name":"University of Siena , , via Aldo Moro 2 , ,","place":["Siena, Italy, 53100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5991-5868","authenticated-orcid":true,"given":"Maria Luisa","family":"Mangoni","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , Piazzale A. Moro 5 , ,","place":["Roma, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"2026090307174774300_cit1","doi-asserted-by":"publisher","first-page":"1574919","DOI":"10.3389\/fped.2025.1574919","article-title":"In-depth analysis of cystic fibrosis cases caused by CFTR gene variation\nand research on the prediction and simulation of the impact on protein\nfunction","volume":"13","author":"Shan","year":"2025","journal-title":"Front. Pediatr."},{"key":"2026090307174774300_cit2","doi-asserted-by":"publisher","first-page":"3978","DOI":"10.3390\/jcm14113978","article-title":"Cystic Fibrosis Transmembrane Conductance Regulator Modulators in\nCystic Fibrosis: A Review of Registry-Based Evidence","volume":"14","author":"Salvatore","year":"2025","journal-title":"J. Clin. Med."},{"key":"2026090307174774300_cit3","doi-asserted-by":"publisher","first-page":"2128","DOI":"10.1021\/acschembio.3c00310","article-title":"CFTR Folding: From Structure and\nProteostasis to Cystic Fibrosis Personalized Medicine","volume":"18","author":"McDonald","year":"2023","journal-title":"ACS Chem. Biol."},{"key":"2026090307174774300_cit4","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1038\/s41586-023-05854-7","article-title":"CFTR function, pathology and pharmacology\nat single-molecule resolution","volume":"616","author":"Levring","year":"2023","journal-title":"Nature"},{"key":"2026090307174774300_cit5","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.cell.2017.06.041","article-title":"Conformational\nChanges of CFTR upon Phosphorylation\nand ATP Binding","volume":"170","author":"Zhang","year":"2017","journal-title":"Cell"},{"key":"2026090307174774300_cit6","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1152\/physrev.00039.2023","article-title":"Lung antimicrobial\nproteins and peptides:\nFrom host defense to therapeutic strategies","volume":"104","author":"Di","year":"2024","journal-title":"Physiol. Rev."},{"key":"2026090307174774300_cit7","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1091\/mbc.e14-04-0935","article-title":"From CFTR biology toward combinatorial pharmacotherapy:\nexpanded classification of cystic fibrosis mutations","volume":"27","author":"Veit","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"2026090307174774300_cit8","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(16)30188-6","article-title":"Classification of CFTR mutation classes","volume":"4","author":"Marson","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"2026090307174774300_cit9","doi-asserted-by":"publisher","first-page":"263","DOI":"10.3390\/arm92040026","article-title":"Cystic Fibrosis: Understanding Cystic Fibrosis Transmembrane\nRegulator Mutation Classification and Modulator Therapies","volume":"92","author":"Anwar","year":"2024","journal-title":"Adv. Respir. Med."},{"key":"2026090307174774300_cit10","doi-asserted-by":"publisher","first-page":"119","DOI":"10.3390\/cimb47020119","article-title":"Unraveling\nthe Mechanism of Action, Binding Sites, and Therapeutic Advances of\nCFTR Modulators: A Narrative Review","volume":"47","author":"Baroni","year":"2025","journal-title":"Curr. Issues\nMol. Biol."},{"key":"2026090307174774300_cit11","doi-asserted-by":"publisher","first-page":"503857","DOI":"10.1016\/j.anpede.2025.503857","article-title":"Advances in\nthe treatment of cystic fibrosis: CFTR modulators","volume":"102","author":"Pastor-Vivero","year":"2025","journal-title":"An Pediatr."},{"key":"2026090307174774300_cit12","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1021\/acs.jmedchem.4c02547","article-title":"Discovery\nand Development of CFTR Modulators for the\nTreatment of Cystic Fibrosis","volume":"68","author":"Wang","year":"2025","journal-title":"J. Med. Chem."},{"key":"2026090307174774300_cit13","doi-asserted-by":"publisher","first-page":"L832","DOI":"10.1152\/ajplung.00287.2024","article-title":"Lumacaftor\ninhibits\nchannel activity of rescued F508del cystic fibrosis transmembrane\nconductance regulator","volume":"328","author":"Ambrosetti","year":"2025","journal-title":"Am. J. Physiol. Lung\nCell Mol. Physiol."},{"key":"2026090307174774300_cit14","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1085\/jgp.201711886","article-title":"T.C. A common mechanism for CFTR\npotentiators","volume":"149","author":"Yeh","year":"2017","journal-title":"J. Gen. Physiol."},{"key":"2026090307174774300_cit15","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.coph.2017.09.015","article-title":"CFTR potentiators:\nfrom bench to bedside","volume":"34","author":"Jih","year":"2017","journal-title":"Curr. Opin. Pharmacol."},{"key":"2026090307174774300_cit16","doi-asserted-by":"publisher","first-page":"17534666251323194","DOI":"10.1177\/17534666251323194","article-title":"Cystic fibrosis:\nnew challenges and perspectives beyond\nelexacaftor\/tezacaftor\/ivacaftor","volume":"19","author":"Terlizzi","year":"2025","journal-title":"Ther. Adv.\nRespir. Dis."},{"key":"2026090307174774300_cit17","doi-asserted-by":"publisher","first-page":"2793","DOI":"10.3390\/cells10102793","article-title":"Therapeutic Approaches\nfor Patients with Cystic Fibrosis\nNot Eligible for Current CFTR Modulators","volume":"10","author":"Fajac","year":"2021","journal-title":"Cells"},{"key":"2026090307174774300_cit18","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1002\/psc.1148","article-title":"Esculentin\n1\u201321: a linear antimicrobial peptide\nfrom frog skin with inhibitory effect on bovine mastitis-causing bacteria","volume":"15","author":"Islas-Rodriguez","year":"2009","journal-title":"J. Pept. Sci."},{"key":"2026090307174774300_cit19","doi-asserted-by":"publisher","first-page":"2773","DOI":"10.1007\/s00018-013-1291-7","article-title":"Esculentin(1\u201321),\nan amphibian skin membrane-active peptide with potent activity on\nboth planktonic and biofilm cells of the bacterial pathogen Pseudomonas\naeruginosa","volume":"70","author":"Luca","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"2026090307174774300_cit20","doi-asserted-by":"publisher","first-page":"4400","DOI":"10.3390\/ijms25084400","article-title":"An Overview\nof Frog Skin-Derived Esc Peptides: Promising Multifunctional Weapons\nagainst Pseudomonas aeruginosa-Induced Pulmonary and Ocular Surface\nInfections","volume":"25","author":"Mangoni","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"2026090307174774300_cit21","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.1007\/s00726-015-2041-y","article-title":"D-Amino acids incorporation in the frog skin-derived\npeptide esculentin-1a(1\u201321)NH2 is beneficial for its multiple\nfunctions","volume":"47","author":"Di Grazia","year":"2015","journal-title":"Amino Acids"},{"key":"2026090307174774300_cit22","doi-asserted-by":"publisher","first-page":"2327","DOI":"10.1016\/j.bbamem.2017.09.009","article-title":"Membrane perturbing activities and\nstructural properties of the frog-skin derived peptide Esculentin-1a(1\u201321)NH(2)\nand its Diastereomer Esc(1\u201321)-1c: Correlation with their antipseudomonal\nand cytotoxic activity","volume":"1859","author":"Loffredo","year":"2017","journal-title":"Biochim. Biophys. Acta,\nBiomembr."},{"key":"2026090307174774300_cit23","doi-asserted-by":"publisher","first-page":"7252","DOI":"10.1128\/AAC.00904-16","article-title":"Esculentin-1a-Derived Peptides Promote Clearance of\nPseudomonas aeruginosa Internalized in Bronchial Cells of Cystic Fibrosis\nPatients and Lung Cell Migration: Biochemical Properties and a Plausible\nMode of Action","volume":"60","author":"Cappiello","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090307174774300_cit24","doi-asserted-by":"publisher","first-page":"8548","DOI":"10.1038\/s41598-017-08361-8","article-title":"In vivo\ntherapeutic efficacy of frog\nskin-derived peptides against Pseudomonas aeruginosa-induced pulmonary\ninfection","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"2026090307174774300_cit25","doi-asserted-by":"publisher","first-page":"2297","DOI":"10.3390\/pharmaceutics14112297","article-title":"Pulmonary Safety\nProfile of Esc Peptides and Esc-Peptide-Loaded Poly(lactide-co-glycolide)\nNanoparticles: A Promising Therapeutic Approach for Local Treatment\nof Lung Infectious Diseases","volume":"14","author":"Cappiello","year":"2022","journal-title":"Pharmaceutics"},{"key":"2026090307174774300_cit26","doi-asserted-by":"publisher","first-page":"701","DOI":"10.3390\/antibiotics13080701","article-title":"The pH-Insensitive\nAntimicrobial and Antibiofilm Activities of the Frog Skin Derived\nPeptide Esc(1\u201321): Promising Features for Novel Anti-Infective\nDrugs","volume":"13","author":"Loffredo","year":"2024","journal-title":"Antibiotics"},{"key":"2026090307174774300_cit27","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/s00018-021-04030-2","article-title":"Esc peptides\nas novel potentiators of defective cystic fibrosis transmembrane conductance\nregulator: an unprecedented property of antimicrobial peptides","volume":"79","author":"Ferrera","year":"2022","journal-title":"Cell. Mol. Life Sci."},{"key":"2026090307174774300_cit28","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s00018-025-05633-9","article-title":"Esc peptides and derivatives potentiate the activity\nof CFTR with gating defects and display antipseudomonal activity in\ncystic fibrosis-like lung disease","volume":"82","author":"Ferrera","year":"2025","journal-title":"Cell. Mol.\nLife Sci."},{"key":"2026090307174774300_cit29","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1124\/mol.106.029926","article-title":"Modulating the folding\nof P-glycoprotein and cystic fibrosis transmembrane conductance regulator\ntruncation mutants with pharmacological chaperones","volume":"71","author":"Wang","year":"2007","journal-title":"Mol. Pharmacol."},{"key":"2026090307174774300_cit30","doi-asserted-by":"publisher","first-page":"22957","DOI":"10.1074\/jbc.270.39.22957","article-title":"Covalent modification of human P-glycoprotein mutants\ncontaining a single cysteine in either nucleotide-binding fold abolishes\ndrug-stimulated ATPase activity","volume":"270","author":"Loo","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2026090307174774300_cit31","doi-asserted-by":"publisher","first-page":"33247","DOI":"10.1074\/jbc.C700175200","article-title":"Correctors promote\nmaturation of cystic fibrosis transmembrane conductance regulator\n(CFTR)-processing mutants by binding to the protein","volume":"282","author":"Wang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2026090307174774300_cit32","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.trsl.2016.10.003","article-title":"Phenylquinoxalinone CFTR activator as potential prosecretory\ntherapy for constipation","volume":"182","author":"Cil","year":"2017","journal-title":"Transl. Res."},{"key":"2026090307174774300_cit33","doi-asserted-by":"publisher","first-page":"4728","DOI":"10.1038\/sj.emboj.7601373","article-title":"In vivo phosphorylation\nof CFTR promotes formation\nof a nucleotide-binding domain heterodimer","volume":"25","author":"Mense","year":"2006","journal-title":"EMBO J."},{"key":"2026090307174774300_cit34","doi-asserted-by":"publisher","first-page":"39620","DOI":"10.1074\/jbc.M407887200","article-title":"The DeltaF508 mutation\ndisrupts packing of the transmembrane segments of the cystic fibrosis\ntransmembrane conductance regulator","volume":"279","author":"Chen","year":"2004","journal-title":"J. Biol.\nChem."},{"key":"2026090307174774300_cit35","doi-asserted-by":"publisher","first-page":"32126","DOI":"10.1074\/jbc.M110.113332","article-title":"Changes in accessibility of cytoplasmic\nsubstances to the pore associated with activation of the cystic fibrosis\ntransmembrane conductance regulator chloride channel","volume":"285","author":"El Hiani","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026090307174774300_cit36","doi-asserted-by":"publisher","first-page":"5493","DOI":"10.3390\/ijms20215463","article-title":"Unravelling the Regions\nof Mutant F508del-CFTR More Susceptible to the Action of Four Cystic\nFibrosis Correctors","volume":"20","author":"Amico","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"2026090307174774300_cit37","doi-asserted-by":"publisher","first-page":"25710","DOI":"10.1016\/S0021-9258(18)47306-1","article-title":"Intracellular turnover of cystic fibrosis transmembrane\nconductance regulator. Inefficient processing and rapid degradation\nof wild-type and mutant proteins","volume":"269","author":"Ward","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2026090307174774300_cit38","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1002\/emmm.201302699","article-title":"Discovery of novel potent DeltaF508-CFTR\ncorrectors\nthat target the nucleotide binding domain","volume":"5","author":"Odolczyk","year":"2013","journal-title":"EMBO\nMol. Med."},{"key":"2026090307174774300_cit39","doi-asserted-by":"publisher","first-page":"616","DOI":"10.3390\/pharmaceutics12070616","article-title":"Cystic Fibrosis: Overview of the\nCurrent Development Trends and Innovative Therapeutic Strategies","volume":"12","author":"Almughem","year":"2020","journal-title":"Pharmaceutics"},{"key":"2026090307174774300_cit40","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1016\/j.jcf.2021.03.011","article-title":"Elexacaftor co-potentiates the activity\nof F508del and gating mutants of CFTR","volume":"20","author":"Veit","year":"2021","journal-title":"J. Cyst\nFibros"},{"key":"2026090307174774300_cit41","doi-asserted-by":"publisher","first-page":"17640","DOI":"10.1038\/s41598-019-54158-2","article-title":"Nanomolar-potency\n\u2018co-potentiator\u2019 therapy for cystic fibrosis caused\nby a defined subset of minimal function CFTR mutants","volume":"9","author":"Phuan","year":"2019","journal-title":"Sci. Rep."},{"key":"2026090307174774300_cit42","doi-asserted-by":"publisher","first-page":"12757","DOI":"10.1073\/pnas.1815287115","article-title":"Molecular\nstructure of the ATP-bound, phosphorylated\nhuman CFTR","volume":"115","author":"Zhang","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026090307174774300_cit43","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1152\/physrev.00007.2018","article-title":"Gating,\nand Regulation of the Cftr\nAnion Channel","volume":"99","author":"Csanady","year":"2019","journal-title":"Physiol. Rev."},{"key":"2026090307174774300_cit44","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.18164","article-title":"Obligate coupling\nof CFTR pore opening\nto tight nucleotide-binding domain dimerization","volume":"5","author":"Mihalyi","year":"2016","journal-title":"Elife"},{"key":"2026090307174774300_cit45","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/s00232-009-9205-1","article-title":"PKA mediates constitutive activation\nof CFTR in human\nsweat duct","volume":"231","author":"Reddy","year":"2009","journal-title":"J. Membr. Biol."},{"key":"2026090307174774300_cit46","doi-asserted-by":"publisher","first-page":"690247","DOI":"10.3389\/fphys.2021.690247","article-title":"Role of Protein Kinase\nA-Mediated Phosphorylation in CFTR Channel Activity Regulation","volume":"12","author":"Della Sala","year":"2021","journal-title":"Front. Physiol."},{"key":"2026090307174774300_cit47","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/nature04712","article-title":"The ABC protein turned chloride channel\nwhose failure causes cystic fibrosis","volume":"440","author":"Gadsby","year":"2006","journal-title":"Nature"},{"key":"2026090307174774300_cit48","doi-asserted-by":"publisher","first-page":"102542","DOI":"10.1016\/j.isci.2021.102542","article-title":"Identification\nof\nbinding sites for ivacaftor on the cystic fibrosis transmembrane conductance\nregulator","volume":"24","author":"Laselva","year":"2021","journal-title":"iScience"},{"key":"2026090307174774300_cit49","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1085\/jgp.201912360","article-title":"Identifying\nthe molecular target sites for CFTR potentiators GLPG1837 and VX-770","volume":"151","author":"Yeh","year":"2019","journal-title":"J. Gen. 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