AI Article Synopsis
- CFTR inhibitors show promise as therapies for cholera by reducing fluid secretion and mortality associated with the disease.
- Researchers created various CFTR inhibitors by linking malonic acid hydrazide to polyethylene glycols, finding that divalent compounds were significantly more effective than monovalent ones.
- Tests in mouse models demonstrated that these inhibitors effectively blocked cholera toxin-induced fluid secretion and improved survival rates in infected mice, suggesting their potential as a safe and cost-effective treatment.
Article Abstract
Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have potential application as antisecretory therapy in cholera. We synthesized mono- and divalent CFTR inhibitors consisting of a malonic acid hydrazide (MalH) coupled via a disulfonic stilbene linker to polyethylene glycols (PEGs; 0.2-100 kDa). IC50 values for CFTR inhibition were 10-15 microM for the monovalent MalH-PEGs, but substantially lower for divalent MalH-PEG-MalH compounds, decreasing from 1.5 to 0.3 microM with increasing PEG size and showing positive cooperativity. Whole-cell patch-clamp showed voltage-dependent CFTR block with inward rectification. Outside-out patch-clamp showed shortened single-channel openings, indicating CFTR pore block from the extracellular side. Luminally added MalH-PEG-MalH blocked by >90% cholera toxin-induced fluid secretion in mouse intestinal loops (IC50 approximately 10 pmol/loop), and greatly reduced mortality in a suckling mouse cholera model. These conjugates may provide safe, inexpensive antisecretory therapy.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322358 | PMC |
| http://dx.doi.org/10.1016/j.chembiol.2008.05.015 | DOI Listing |
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