The human Lon protease (hLon) plays an important role to clear oxidized proteins and to maintain mitochondrial homeostasis in relation to the high level of reactive oxygen species (ROS) produced. The basic processes by which hLon works are still mostly unknown but its role has been linked to several conditions including aging, neurodegeneration, and cancer. Central to fully characterize these functional roles is the design of novel compounds that are able to modulate the activity of the human Lon protease. Besides unselective molecules like tripterpenoids and coumarin-based ligands, no specific and mitochondrial-permeable  inhibitors of the hLon are available yet.In our efforts to discover new hLon modulating agents, we have used structure-based molecular design techniques to screen in silico compounds bearing novel chemical scaffolds. Here we present the biological characterization of new indole-based compounds that inhibit protease, peptidase and ATPase activities of the hLon in the low micromolar concentration. The mitochondrial activity of these compounds was tested on HeLa cells and compared to HeLa cells with hLon depleted, demonstrating their permeability to mitochondrial membranes. The use of these compounds will help to understand the role of hLon in the maintenance of the mitochondrial proteome and genome, to study biological effects on processes like mitochondrial functionality, apoptosis, cell proliferation and senescence and, finally, as new lead compound for pharmaceutical development.

Indole-based inhibitors of the mitochondrial human Lon protease

247th National Meeting (2014)

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