SLC26A3 inhibitor identified in small molecule screen blocks colonic fluid absorption and reduces constipation
Open accessAbstract
SLC26A3 (downregulated in adenoma; DRA) is a Cl – /anion exchanger expressed in the luminal membrane of intestinal epithelial cells, where it facilitates electroneutral NaCl absorption. SLC26A3 loss of function in humans or mice causes chloride-losing diarrhea. Here, we identified slc26a3 inhibitors in a screen of 50,000 synthetic small molecules done in Fischer rat thyroid (FRT) cells coexpressing slc26a3 and a genetically encoded halide sensor. Structure-activity relationship studies were done on the most potent inhibitor classes identified in the screen: 4,8-dimethylcoumarins and acetamide-thioimidazoles. The dimethylcoumarin DRA inh -A250 fully and reversibly inhibited slc26a3-mediated Cl – exchange with HCO 3 – , I – , and thiocyanate (SCN – ), with an IC 50 of ~0.2 μM. DRA inh -A250 did not inhibit the homologous anion exchangers slc26a4 (pendrin) or slc26a6 (PAT-1), nor did it alter activity of other related proteins or intestinal ion channels. In mice, intraluminal DRA inh -A250 blocked fluid absorption in closed colonic loops but not in jejunal loops, while the NHE3 (SLC9A3) inhibitor tenapanor blocked absorption only in the jejunum. Oral DRA inh -A250 and tenapanor comparably reduced signs of constipation in loperamide-treated mice, with additive effects found on coadministration. DRA inh -A250 was also effective in loperamide-treated cystic fibrosis mice. These studies support a major role of slc26a3 in colonic fluid absorption and suggest the therapeutic utility of SLC26A3 inhibition in constipation.
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DRAinh-A250 blocked fluid absorption in mouse colonic loops and reversed loperamide-induced constipation when administered intraluminally.
“When administered intraluminally, DRAinh-A250 blocked fluid absorption in mouse colonic loops and reversed loperamideinduced constipation”
From Irritable bowel syndrome (2020) · cites this paper as [140]
The distal-colon loop results report that DRAinh-A250 administered directly into mouse colonic loops prevented fluid absorption. The constipation results, however, describe oral administration that partially prevented loperamide-induced reductions in stool measures—not intraluminal administration that reversed established constipation. (LLM, conf=0.91)
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Diagnosis and management of chronic constipation in adults
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Cited by
Sorted by citations
Ford, A. C., Sperber, A. D., Corsetti, M., & Camilleri, M. (2020) · The Lancet · doi:10.1016/s0140-6736(20)31548-8 · Cited by 818 · see citing works
- Authors
- Haggie, P. M., Cil, O., Lee, S., Tan, J.-A., Rivera, A. A., Phuan, P.-W., & Verkman, A. S.
- Affiliations
- Department of Medicine,
- University of California, San Francisco (US)
- Corresponding author
- Haggie, Peter M.
- Verkman, Alan S.
- Venue
- JCI Insight
- Published
- 2018-07-26
- Volume
- 3
- Issue
- 14
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC6124422
- OpenAlex
- W2883970497
- Cited by
- 56
- References
- 1
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 9 · 2022: 5 · 2021: 9 · 2020: 6 · 2019: 9
- FWCI
- 5.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIDDK, NEI, Cystic Fibrosis Foundation, Cystic Fibrosis Research Inc. (DK099803,DK72517,DK101373,EY13573,CFF,R613,CFRI New Horizons)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- SLC26A3, chloride exchange, constipation, small molecule inhibitors, tenapanor, NHE3 inhibition, loperamide, cystic fibrosis, intestinal epithelium
- MeSH terms
- Sodium-Hydrogen Exchanger 3, Sulfate Transporters, Animals, Chlorides, Constipation, Cystic Fibrosis, Disease Models, Animal, Drug Evaluation, Preclinical, Epithelial Cells, Humans, Loperamide, Rats, Inbred F344, Ion Transport, Antiporters, Chloride-Bicarbonate Antiporters, Mice, Rats, High-Throughput Screening Assays, HEK293 Cells
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