2.B.119.  The Cereulide K+ Carrier (Cereulide) Family

The cyclic depsipeptide cereulide is a natural potassium ionophore that is highly cytotoxic toward pancreatic β-cells, altering insulin secretion upon prolonged low-dose exposure. Mimicking the natural cereulide structure, García-Calvo et al. 2019 designed and synthesized analogous artificial cyclic depsipeptide 1.  Lipid bilayer assays revealed that it has high K⁺/Na⁺ selectivity (S_K⁺/S_Na⁺ = 8 without FCCP, increased to 129 with FCCP), and transport activity enhanced by FCCP, while the other three cyclic peptides displaied lower selectivity but strong K⁺ transport efficiencies. To evaluate their impact on glucose-stimulated insulin secretion, the effects of these four cyclic peptides were examined in INS1E insulinoma cells (Yuan et al. 2024). The findings revealed that the negatively charged macrocycle compound consistently promoted insulin secretion from tumour islet β-cells, whereas the positively charged ones inhibit glucose-stimulated insulin release. It was hypothesized that these opposing regulatory effects on insulin secretion stem from different transport mechanisms. Acting as a selective potassium/proton antiporter with low transport activity, 1 readily achieved electroneutral transport. This diminished membrane depolarization, activated a mitochondrial function, stimulated ATP production, and facilitated insulin release. These results demonstrate the ability to manipulate the structure and transport mechanism of natural cereulide to develop novel artificial potassium ion carriers with pharmacological significance (García-Calvo et al. 2019). This and other K⁺ ionophores have been reviewed (Yuan et al. 2024).