Mapping the N-Terminal Hexokinase-I Binding Site onto Voltage-Dependent Anion Channel-1 To Block Peripheral Nerve Demyelination.

Benoit Gautier, Mélanie Forêt Jacquard, Sophie Guelfi, Scarlette Abbou, Elisa Gonzalez, Jade Berthelot, Hassan Boukhaddaoui, Aurélien Lebrun, Baptiste Legrand, Nicolas Tricaud, Nicolas Inguimbert

Journal of medicinal chemistry 2022 Sep 08

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The voltage-dependent anion channel (VDAC), the most abundant protein on the outer mitochondrial membrane, is implicated in ATP, ion and metabolite exchange with cell compartments. In particular, the VDAC participates in cytoplasmic and mitochondrial Ca2+ homeostasis. Notably, the Ca2+ efflux out of Schwann cell mitochondria is involved in peripheral nerve demyelination that underlies most peripheral neuropathies. Hexokinase (HK) isoforms I and II, the main ligands of the VDAC, possess a hydrophobic N-terminal structured in α-helix (NHKI) that is necessary for the binding to the VDAC. To gain further insight into the molecular basis of HK binding to the VDAC, we developed and optimized peptides based on the NHKI sequence. These modifications lead to an increase of the peptide hydrophobicity and helical content that enhanced their ability to prevent peripheral nerve demyelination. Our results provide new insights into the molecular basis of VDAC/HK interaction that could lead to the development of therapeutic compounds for demyelinating peripheral neuropathies.

Citation

Benoit Gautier, Mélanie Forêt Jacquard, Sophie Guelfi, Scarlette Abbou, Elisa Gonzalez, Jade Berthelot, Hassan Boukhaddaoui, Aurélien Lebrun, Baptiste Legrand, Nicolas Tricaud, Nicolas Inguimbert. Mapping the N-Terminal Hexokinase-I Binding Site onto Voltage-Dependent Anion Channel-1 To Block Peripheral Nerve Demyelination. Journal of medicinal chemistry. 2022 Sep 08;65(17):11633-11647