Ca2+ dependent arrhythmias are a critical feature of conditions such as CPVT, ischemia and atrial fibrillation. TRPM4 is a Ca2+ activated cation channel and an interesting drug target for the prevention and suppression of this type of arrhythmias. To date, the only in vivo applicable blockers of TRPM4 are meclofenamate and glibenclamide, which have obviously other prominent targets and have a relatively low efficacy to block TRPM4. Therefore, we aim to design a new class of high-affinity TRPM4 blockers, and determine the role of TRPM4 in tissue with high-translational value. Specifically, we aim to: i) to define the binding site for meclofenamate by CryoEM, in order to delineate the binding pocket for inhibitors on the TRPM4 protein. Based on this information we will create an in silico model that will be used to ii) identify new compounds with high affinity using an ultra-large scale virtual screen and structure-activity relation optimisation of meclofenamate through medicinal chemistry, and iii) test the effect of novel compounds and meclofenamate in human iPSC derived cardiomyocytes, and in living guinea pigs. Taken together, this project will deliver new insight in the mechanism of block of TRPM4, and the translational potential of TRPM4 targeting as a strategy to prevent cardiac arrhythmias.
Cooperations:: Professor Dr. Marc Freichel; Professor Dr. Manuel A. Friese; Professor Dr. Christian Klein; Professor Rudi Vennekens, Ph.D. (Belgien)