Development of IKs activating compounds for treatment of long QT syndrome.

Abstract

The purpose of this study is to optimize the therapeutic potential of IKs (KCNQ1/KCNE1) channel activating polyunsaturated fatty acids (PUFAs) by using computational and experimental methods to increase their potency and specificity. We are interested in activating the IKs channel because loss of function mutations in this channel can cause long QT syndrome, specifically type 1 (LQT1). LQT1 can lead to certain cardiac arrhythmia and even sudden cardiac death. We hypothesized that using computational methods, such as site identification by ligand competitive saturation (SILCS), combined with physiological experiments will provide sufficient information for us to edit our PUFA structures to enhance their binding affinities and thus IKs activation. We recently developed a new compound using these methods that has increased activation effects and affinity for the IKs channel and we are now working to optimize this further.