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Allosteric modulation and ligand binding kinetics at the Kv11.1 channel

Promotor: Prof.dr. A.P. IJzerman, Co-Promotor: L.H. Heitman

Z. Yu
20 oktober 2015
Thesis in Leiden Repository

Kv11.1-induced cardiotoxicity has emerged as an unanticipated adverse effect of many pharmacological agents and has become a major obstacle in drug development over the past decades. In this thesis, allosteric modulation of the Kv11.1 channel has been extensively explored, and negative allosteric modulators were shown to relieve the proarrhythmic effects of structurally and therapeutically diverse Kv11.1 blockers. The most potent modulators may be developed as a new class of antiarrhythmic medications in the future. On the other hand, kinetic binding parameters of a wide range of Kv11.1 blockers at the channel have been thoroughly investigated in this thesis. Association and dissociation rates or residence times are strongly suggested to be integrated with equilibrium affinity values into the future paradigms for a better and more comprehensive evaluation of Kv11.1 liability of drug candidates. The “kon-koff-KD” kinetic map provides a first and promising classification of Kv11.1 blockers, which could be beneficial and indicative for drug researchers to design compounds with less Kv11.1-mediated cardiac side effects in the early stage of drug development. Hopefully, all findings in this thesis have brought new insights into Kv11.1-induced cardiac arrhythmias, and will offer opportunities for restoring or preventing this kind of arrhythmias in the near future.

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