Development of peptide modulators targeting proteinprotein interactions of the Sodium Leak Channel Complex

We found that the N-terminal and middle half (120 AA) of the DII-DIII linker also inhibited NALCN currents, while the C-terminal half was not as efficient.Shortening the construct further (60 AA) abolished the effect.-100 -80 -60 -40 -20 20 40 60 80 100 -0.2 0.2 0.4 0.6 0.8 1.0 1.2 I / Imax mV + Linear-3R NALCN + Linear + Cyclic-3R The Sodium leak channel, non-selective (NALCN) conducts a current of monovalent cations into neurons thereby adjusting the membrane potential and excitability.(PMID: 17448995) NALCN consists of 4 domains connected by intracellular linkers.The DI-DII linker forms a loop which binds to a hydrophobic surface of uncoordinated protein-79 (UNC79).The DII-DIII linker forms alpha helical structures which interact with uncoordinated protein-80 (UNC80).(PMID: 32494638).Mutations in NALCN, UNC79 and UNC80 are rare in humans but cause severe neurodevelopmental symptoms.(PMID: 30167850) Here, we aim to use the linker structures as a starting point to develop complex inhibiting peptides.