Background-Defective protein trafficking is a consequence of gene mutations. Human long-QT (LQT) syndrome results from mutations in several genes, including the human ether-a-go-go-related gene (HERG), which encodes a delayed rectifier K ϩ current. Trafficking-defective mutant HERG protein is a mechanism for reduced delayed rectifier K ϩ current in LQT2, and high-affinity HERG channel-blocking drugs can result in pharmacological rescue. Methods and Results-We postulated that drug molecules

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... ied to remove high-affinity HERG block may still stabilize mutant proteins in a conformation required for rescue. We tested terfenadine carboxylate (fexofenadine) and terfenadine, structurally similar drugs with markedly different affinities for HERG block, for rescue of traffickingdefective LQT2 mutations. Terfenadine rescued the N470D mutation but blocked the channels. In contrast, fexofenadine rescued N470D with a half-maximal rescue concentration of 177 nmol/L, which is Ϸ350-fold lower than the half-maximal channel block concentration. The G601S mutation was also rescued without channel block. Conclusions-Pharmacological rescue can occur without channel block. This could represent a new antiarrhythmic paradigm in the treatment of some trafficking-defective LQT2 mutations. (Circulation. 2002;105:2830-2835.)