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A novel SLC26A9 inhibitor, S9-A13, reveals a minor contribution of SLC26A9 to constitutive airway chloride secretion
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  • Sungwoo Jo,
  • Raquel Centeio,
  • Jinhong Park,
  • Jiraporn Ousingsawat,
  • Dong-kyu Jeon,
  • Khaoula Talbi,
  • Rainer Schreiber,
  • Kunhi Ryu,
  • Wan Namkung,
  • Karl Kunzelmann
Sungwoo Jo
Yonsei University College of Pharmacy
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Raquel Centeio
Universität Regensburg
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Jinhong Park
Yonsei University
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Jiraporn Ousingsawat
Universität Regensburg
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Dong-kyu Jeon
Yonsei University
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Khaoula Talbi
Universität Regensburg
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Rainer Schreiber
Universität Regensburg
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Kunhi Ryu
Yonsei University
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Wan Namkung
Yonsei University
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Karl Kunzelmann
Universität Regensburg

Corresponding Author:[email protected]

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Abstract

Background and purpose: The solute carrier 26 family member A9 (SLC26A9) is an epithelial anion transporter that is assumed to contribute to basal airway chloride conductance and airway surface hydration. It is a genetic modifier in cystic fibrosis and therefore may serve as a possible alternative Cl- secretory pathway in airways. Whether SLC26A9 or CFTR is responsible for airway Cl- transport under basal conditions, is still unclear, due to the lack of a specific inhibitor for SLC26A9. Experimental approach: In the present study we report a novel potent and specific inhibitor for SLC26A9, which was identified by screening of a drug-like small molecule library and subsequent chemical modifications. Key results: The most potent compound S9-A13 inhibited SLC26A9 with an IC50 of 90.9  13.4 nM in YFP fluorescence quenching assay. Notably, S9-A13 did not inhibit other members of the SLC26-family and showed little effects on other Cl- channels such as CFTR, TMEM16A, and VRAC. Although S9-A13 clearly inhibited SLC26A9 when overexpressed in HEK293 cells, it showed little inhibitory effects on ion transport in highly differentiated human airway epithelial cells or mouse trachea under basal conditions, despite clear apical expression of SLC26A9 in ciliated epithelial cells. Conclusions and Implications: Using the potent inhibitor S9-A13, the present data demonstrate the lack of activity of SLC26A9 in nonstimulated airways. Because on the contrary, the CFTR-inhibitor CFTRinh-172 clearly inhibited transport in non-stimulated airways, we conclude that CFTR rather than SLC26A9 is in charge of constitutive Cl- transport in airways.