Poly(ethylene glycol) as a scaffold for high-affinity open-channel blockers of the mouse nicotinic acetylcholine receptor.

Wan-Chen Lin,Stuart Licht,Valentin Ceña

doi:10.1371/journal.pone.0112088

Wan-Chen Lin, Stuart Licht + Show 1 more

Open Access

https://doi.org/10.1371/journal.pone.0112088

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Journal: PloS one	Publication Date: Nov 11, 2014
Citations: 1	License type: CC BY 4.0

Affiliation: Massachusetts Institute of Technology

Abstract

High-affinity blockers for an ion channel often have complex molecular structures that are synthetically challenging and/or laborious. Here we show that high-affinity blockers for the mouse nicotinic acetylcholine receptor (AChR) can be prepared from a structurally simple material, poly(ethylene glycol) (PEG). The PEG-based blockers (PQ1–5), comprised of a flexible octa(ethylene glycol) scaffold and two terminal quaternary ammonium groups, exert low- to sub-micromolar affinities for the open AChR pore (measured via single-channel analysis of AChRs expressed in human embryonic kidney cells). PQ1–5 are comparable in pore-binding affinity to the strongest AChR open-channel blockers previously reported, which have complex molecular structures. These results suggest a general approach for designing potent open-channel blockers from a structurally flexible polymer. This design strategy involves simple synthetic procedures and does not require detailed information about the structure of an ion-channel pore.

Highlights

Ion channels play important roles in diverse physiological processes, including neuronal signaling [1], cardiac rhythm setting [2], and insulin secretion [3]
The proposed acetylcholine receptor (AChR) blockers comprise: (1) a flexible polymeric backbone that is capable of adopting favorable conformations to interact with the pore interior; and (2) one or more quaternary ammonium (QA) groups that interact with the transmembrane electric field and direct the molecule to target the open pore [8]
The proposed strategy was first tested using a series of PEGtrimethylammonium conjugates [8]

Summary

Introduction

Ion channels play important roles in diverse physiological processes, including neuronal signaling [1], cardiac rhythm setting [2], and insulin secretion [3]. Rational design of open-channel blockers has been challenging due to the limited availability of high-resolution structures for the ion-conducting pores. We report the synthesis and functional characterizations of polyethylene glycol (PEG)-based open-channel blockers of the nicotinic AChR that both achieve high pore-binding affinities (comparable to those of natural pore-blocking toxins) and possess simple, readily accessible molecular structures.

Results

Conclusion