Hydraphiles are a class of synthetic ion channels that now have a twenty-year history of analysis and success. In early studies, these compounds were rigorously validated in a wide range of in vitro assays including liposomal ion flow detected by NMR or ion-selective electrodes, as well as biophysical experiments in planar bilayers. During the past decade, biological activity was observed for these compounds including toxicity to bacteria, yeast, and mammalian cells due to stress caused by the disruption of ion homeostasis. The channel mechanism was verified in cells using membrane polarity sensitive dyes, as well as patch clamping studies. This body of work has provided a solid foundation with which hydraphiles have recently demonstrated acute biological toxicity in the muscle tissue of living mice, as measured by whole animal fluorescence imaging and histological studies. Here we review the critical structure-activity relationships in the hydraphile family of compounds and the in vitro and in cellulo experiments that have validated their channel behavior. This report culminates with a description of recently reported efforts in which these molecules have demonstrated activity in living mice. 1. Introduction The outer membranes of organisms serve to enclose the functioning cell and separate it from the external environment [1]. This vital protective function is complicated by the need for the cell to permit the entry of nutrients and the egress of waste products. It is unclear what were the earliest barriers that permitted separate cells to evolve and ultimately to combine into higher life forms [2, 3]. Indeed, there is considerable scholarly effort currently underway in this area. What is clear is that along with the development of protective or confining membranes, structures and mechanisms had to evolve [4] that would permit selective passage of ions and molecules through them [5]. Today, the proteins that regulate ion balance and transmembrane transport are extremely complex molecules that interact directly with the membranes in which they are embedded, and they exhibit remarkable selectivity (specificity) in their chemical functions [6]. During the past two decades, considerable effort has been expended to develop synthetic amphiphiles that will insert into membranes and exhibit at least some of the functions of highly complex protein channels [7, 8]. There has been considerable success in this arena, and a number of reviews describe the efforts [9–13]. Our own effort in this area initially involved the compounds we have called “hydraphiles” [14].
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