Targeted stabilization of Munc18-1 function via pharmacological chaperones

Abramov D, Guiberson NGL, Daab A, Na Y, Petsko GA, Sharma M, Burre J.

EMBO Molecular Medicine, 2020


The authors identified two structure-based drug designs that bind to wild-type and mutant Munc18-1 and revert the neuronal dysfunction as a potential targeted treatment against severe pediatric encephalopathies.  The treatment was evaluated both in vivo and in vitro.

The Maestro Pro MEA system was used to evaluate the neural activity of mouse cortical neurons in order to determine if compounds 9, 10 and 13 were able to rescue the neuronal activity of Mucn18-1 knockout neurons before and after the addition on the compounds.  Compounds 9 and 13 were shown to increase the significantly increase the mean firing frequency in G544D Munch18-1 neurons while compound 10 lead to a significant decrease in mean firing frequency at high concentrations.