Structure-based identification of optimized mutant Kir3.4 inhibitors for renoprotection (C07 (A03 + A04))

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Somatic and germline mutations in the K+ channel gene KCNJ5 (Kir3.4) cause aldosterone-producing adenomas and familial hyperaldosteronism, respectively. Using cryo-electron microscopy, we aim to elucidate the structures of WT and mutant Kir3.4. Based on structural information, we will refine specific inhibitors of mutant Kir3.4 or identify new inhibitors with optimized properties. We will test their inhibitory potential in vitro and in vivo, using a previously established pig model with KCNJ5 mutation. This will allow us to understand molecular mechanisms of Kir3.4 channel dysfunction and optimize inhibitors for the diagnosis (based on a drop in aldosterone upon short-term administration) and long-term therapy (leading to tumor shrinkage) of patients with KCNJ5 mutations.