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 μM for the monovalent MalH-PEGs, but substantially lower for divalent MalH-PEG-MalH compounds, decreasing from 1.5 to 0.3 μM 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 ∼10 pmol/loop), and greatly reduced mortality in a suckling mouse cholera model. These conjugates may provide safe, inexpensive antisecretory therapy.
| Original language | English |
|---|---|
| Pages (from-to) | 718-728 |
| Number of pages | 11 |
| Journal | Chemistry and Biology |
| Volume | 15 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Jul 21 2008 |
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Keywords
- CELLBIO
- CHEMBIO
- SIGNALING
ASJC Scopus subject areas
- Organic Chemistry
Cite this
Nanomolar CFTR Inhibition by Pore-Occluding Divalent Polyethylene Glycol-Malonic Acid Hydrazides. / Sonawane, N. D.; Zhao, Dan; Zegarra-Moran, Olga; Galietta, Luis J V; Verkman, A. S.
In: Chemistry and Biology, Vol. 15, No. 7, 21.07.2008, p. 718-728.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Nanomolar CFTR Inhibition by Pore-Occluding Divalent Polyethylene Glycol-Malonic Acid Hydrazides
AU - Sonawane, N. D.
AU - Zhao, Dan
AU - Zegarra-Moran, Olga
AU - Galietta, Luis J V
AU - Verkman, A. S.
PY - 2008/7/21
Y1 - 2008/7/21
N2 - 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 μM for the monovalent MalH-PEGs, but substantially lower for divalent MalH-PEG-MalH compounds, decreasing from 1.5 to 0.3 μM 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 ∼10 pmol/loop), and greatly reduced mortality in a suckling mouse cholera model. These conjugates may provide safe, inexpensive antisecretory therapy.
AB - 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 μM for the monovalent MalH-PEGs, but substantially lower for divalent MalH-PEG-MalH compounds, decreasing from 1.5 to 0.3 μM 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 ∼10 pmol/loop), and greatly reduced mortality in a suckling mouse cholera model. These conjugates may provide safe, inexpensive antisecretory therapy.
KW - CELLBIO
KW - CHEMBIO
KW - SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=47049088617&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=47049088617&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2008.05.015
DO - 10.1016/j.chembiol.2008.05.015
M3 - Article
VL - 15
SP - 718
EP - 728
JO - Chemistry and Biology
JF - Chemistry and Biology
SN - 1074-5521
IS - 7
ER -