Compounds specifically enhance I Ks by modulating VSD-pore coupling.

IKs, a slow delayed rectifier current, is carried by the KCNQ1 channel and KCNE1 regulatory subunit, and is important for terminating cardiac action potentials. Upon membrane depolarization, KCNQ1 opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. KCNE1 specifically suppresses the IO state so that the IKs channel only opens to the AO state. The AO state is therefore more physiologically important in the heart. Previous studies from our lab and other labs have shown that IKs activators can be safe and effective in treating cardiac arrhythmias. The goal of this study is to find a novel strategy for specifically enhancing the AO state, thereby enhancing IKs in the heart but not KCNQ1 channels in other tissues that are not associated with KCNE1. We have identified sites in the KCNQ1 channel that are essential for VSD-pore coupling at the AO state. In silico screening by docking a library of compounds to these sites in the KCNQ1 channel structure and subsequent testing of the hit compounds using electrophysiology identified compounds that enhance IKs. Among these compounds, CC6 and CA1 specifically and potently increased the amplitude of IKs, but have minimal effects on the currents when KCNQ1 was expressed alone. These results provide an example of drugs with great selectivity for modulating IKs channels by targeting the mechanism of VSD-pore coupling of the AO state. Low specificity of some currently used antiarrhythmic drugs in clinics is known to induce severe side effects in patients, limiting the potential for further development of antiarrhythmic drugs. Our results suggest that a gating-mechanism-based rational drug screening provides a novel strategy for developing safe and effective antiarrhythmic drugs.