Ion Channels as Therapeutic Targets: A Drug Discovery Perspective

Abstract

Ion channels are membrane proteins expressed in almost all living cells. The sequencing of the human genome has identified more than 400 putative ion channels, but only a fraction of these have been cloned and functionally tested. The widespread tissue distribution of ion channels, coupled with the plethora of physiological consequences of their opening and closing, makes ion-channel-targeted drug discovery highly compelling. However, despite some important drugs in clinical use today, as a class, ion channels remain underexploited in drug discovery and many existing drugs are poorly selective with significant toxicities or suboptimal efficacy. This Perspective seeks to review the ion channel family, its structural and functional features, and the diseases that are known to be modulated by members of the family. In particular, we will explore the structure and properties of known ligands and consider the future prospects for drug discovery in this challenging but high potential area.

On the role of water density fluctuations in the inhibition of a proton channel

“…Ion channels are responsible for a number of channelopathies (i.e., pathological conditions of various origins), including genetic channelopathies caused by malfunctioning ion channels (78). Nevertheless, despite recent efforts resulting in the discovery of novel potential drugs targeting ion channels (39,40), this class of proteins remains quite underexploited in drug discovery because it poses significant challenges (78)(79)(80)(81). For many years,…”

Ion channel therapeutics for pain

“…7 As with many compounds possessing polypharmacology, safety side effects of non-selective agents limit their chronic usage. 8 A commercially successful compound, Gabapentin (3) 9 ( Fig. 2), was discovered using this "phenotypic" method.…”

“…A more recent understanding of which sodium channels are expressed in nociceptors and the generation of experimental and/or genetic data linking specific Nav receptors to a pain phenotype, has spurred the pain research community to deliver selective sodium inhibitors for clinical characterization. Advances in automated in vitro electrophysiology screening platforms 8 have greatly facilitated these research efforts, enabling high quality Nav isoform data to be generated in a high through-put fashion.…”

In pursuit of an inhibitory drug for the proton channel

“…The following protein families are overrepresented: rhodopsin-like G protein-coupled receptors, voltagegated ion channels, and ligand-gated ion channels (1). Their membrane localization, diverse tissue distribution, and the critical roles played by ion channels in human physiology makes these proteins attractive targets for drug discovery (2). Although worldwide sales of ion channel-targeted drugs are over US$10 billion, ion channels remain significantly underexploited as therapeutic targets (3).…”

“…Many ion channel drugs and drug candidates retained relatively low potency, specifically within the range of 0.1-5 μM even after extensive optimization (2). This situation is possibly a reflection of the current level of the drug discovery process for ion channels, where many potential targets have not yet been cloned, making screening campaigns impossible, or when possible, resulting in the identification of poor quality leads (2). Something similar occurred during early stages of kinase drug discovery, in which just a small subset of targets received a large amount of attention and good drugs eventually appeared.…”