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Taming unruly chloride channel inhibitors with rational design [Pharmacology]

A selective inhibitor is a drug that inhibits the function of one type of protein more than others. This precise block of function can reveal the physiological role of the targeted endogenous protein. In PNAS, Koster et al. (1) describe the design and characterization of inhibitors that distinguish between closely related CLC chloride channel proteins. This is a boon to studies of CLC physiological function. In this Commentary, we discuss why selective inhibitors represent a scientific breakthrough, how these well-behaved inhibitors evolved from problematic CLC pharmacophores, and what this work portends for the field. Selective inhibitors of protein function are uniquely valuable tools for studying physiological function. Before the era of molecular biology, inhibitors were the primary, if not only, means of testing the functional significance of proteins. Now, full genomes are sequenced, and a dizzying array of genetic means are available to distinguish protein functions. However, selective inhibitors remain as valuable as ever. Genetic manipulation of protein function is of course phenomenally useful. However, genetic manipulation takes time to implement and always perturbs endogenous physiology. Pharmacology remains irreplaceable as a means of manipulating endogenous function within the time frame of a physiological experiment. As evidence for this claim, the physiological function of proteins with known inhibitors are generally well understood, but the functions of those without inhibitors often remain mysterious. A selective inhibitor for a protein can enable rigorous testing of squishy physiological hypotheses. Examples of selective inhibitors leading to scientific breakthroughs abound. A classic example is how the selective inhibition of the Na+/K+ ATPase by the cardiac glycoside ouabain revealed that sodium and potassium gradients are established by the same ion pump. Soon after, selective inhibition of sodium currents by the paralytic poison tetrodotoxin provided strong evidence that sodium and potassium currents flow through separate … [↵][1]1To whom correspondence should be addressed. Email: jsack{at} [1]: #xref-corresp-1-1

Authors:   Rebecka J. Sepela; Jon T. Sack
Journal:   Proceedings of the National Academy of Sciences current issue
Volume:   115
edition:   21
Year:   2018
Pages:   5311
DOI:   10.1073/pnas.1805589115
Publication date:   22-May-2018
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