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Small molecule anionophores promote transmembrane anion permeation matching CFTR activity Hernando Santa Cruz, Elsa Capurro, Valeria Cossu, Claudia Fiore, Michele García Valverde, María Soto Cerrato, Vanessa Pérez Tomás, Ricardo Moran, Óscar Zegarra Moran, Olga Quesada Pato, Roberto Química orgánica Chemistry, Organic Anion selective ionophores, anionophores, are small molecules capable of facilitating the transmembrane transport of anions. Inspired in the structure of natural product prodigiosin, four novel anionophores 1a-d, including a 1,2,3-triazole group, were prepared. These compounds proved highly efficient anion exchangers in model phospholipid liposomes. The changes in the hydrogen bond cleft modified the anion transport selectivity exhibited by these compounds compared to prodigiosin and suppressed the characteristic high toxicity of the natural product. Their activity as anionophores in living cells was studied and chloride efflux and iodine influx from living cells mediated by these derivatives was demonstrated. These compounds were shown to permeabilize cellular membranes to halides with efficiencies close to the natural anion channel CFTR at doses that do not compromise cellular viability. Remarkably, optimal transport efficiency was measured in the presence of pH gradients mimicking those found in the airway epithelia of Cystic Fibrosis patients. These results support the viability of developing small molecule anionophores as anion channel protein surrogates with potential applications in the treatment of conditions such as Cystic Fibrosis derived from the malfunction of natural anion transport mechanisms. European Union’s Horizon 2020 research and innovation programme under grant agreement No. 667079, La Marató de TV3 Foundation (20132730), Consejería de Educación de la Junta de Castilla y León (Projects BU340U13 and BU092U16) 2018-08-21T08:54:14Z 2018-08-21T08:54:14Z 2018-02 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 2045-2322 http://hdl.handle.net/10259/4873 10.1038/s41598-018-20708-3 eng Scientific Reports. 2018, 8, art. 2608 https://doi.org/10.1038/s41598-018-20708-3 info:eu-repo/grantAgreement/EC/H2020/667079 info:eu-repo/grantAgreement/TV3Foundation/20132730 info:eu-repo/grantAgreement/JCyL/BU340U13 info:eu-repo/grantAgreement/JCyL/BU092U16 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf Nature Research https://riubu.ubu.es/bitstream/10259/4873/7/Hernando-SR_2018.pdf.jpg Hispana TEXT http://creativecommons.org/licenses/by/4.0/ RIUBU. Repositorio Institucional de la Universidad de Burgos http://hdl.handle.net/10259/4873