Nanomolar CFTR Inhibition by Pore-Occluding Divalent Polyethylene Glycol-Malonic Acid Hydrazides
作者： N.D. Sonawane , Dan Zhao , Olga Zegarra-Moran , Luis J.V. Galietta , A.S. Verkman
DOI: 10.1016/J.CHEMBIOL.2008.05.015
关键词:
摘要: Summary 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 a malonic acid hydrazide (MalH) coupled via disulfonic stilbene linker to polyethylene glycols (PEGs; 0.2–100 kDa). IC 50 values for inhibition were 10–15 μM monovalent MalH-PEGs, but substantially lower MalH-PEG-MalH compounds, decreasing from 1.5 0.3 with increasing PEG size showing positive cooperativity. Whole-cell patch-clamp showed voltage-dependent block inward rectification. Outside-out shortened single-channel openings, indicating pore extracellular side. Luminally added blocked by >90% cholera toxin-induced fluid secretion mouse intestinal loops (IC ∼10 pmol/loop), greatly reduced mortality suckling model. These conjugates may provide safe, inexpensive therapy.
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