Engineered specific and high-affinity inhibitor for a subtype of inward-rectifier K+ channels

Abstract

Inward-rectifier K+ (Kir) channels play many important biological roles and are emerging as important therapeutic targets. Subtype-specific inhibitors would be useful tools for studying the channels' physiological functions. Unfortunately, available K+ channel inhibitors generally lack the necessary specificity for their reliable use as pharmacological tools to dissect the various kinds of K+ channel currents in situ. The highly conserved nature of the inhibitor targets accounts for the great difficulty in finding inhibitors specific for a given class of K+ channels or, worse, individual subtypes within a class. Here, by modifying a toxin from the honey bee venom, we have successfully engineered an inhibitor that blocks Kir1 with high (1 nM) affinity and high (>250-fold) selectivity over many commonly studied Kir subtypes. This success not only yields a highly desirable tool but, perhaps more importantly, demonstrates the practical feasibility of engineering subtype-specific K+ channel inhibitors. © 2008 by The National Academy of Sciences of the USA.