Protein modeling to identify functional isoforms of TPP1 and small molecule docking to treat CLN2 disease
Late infantile neuronal ceroid lipofuscinosis is a deadly childhood neurodegenerative disorder caused by the malfunctioning protein TPP1 coded by the gene CLN2. Mutations of TPP1 protease fail to travel from its synthesis location (ER) to the lysosome and therefore cannot break down any peptides or proteins. CLN2 is currently being treated with intraventricular infusions of a recombinant form of TPP1, but this treatment is incredibly invasive with high risk of side effects. No drugs have yet been identified that can pass the blood-brain barrier (BBB) and restore function to TPP1 through intravenous methods, but we believe we will be able to narrow down the search through use of de novo protein modeling and docking. Here we show we can develop accurately folded protein models with which we can identify druggable pockets near structures of interest and use docking to find drugs that can likely bind to TPP1 and its isoforms. Further research must be done to confirm these drugs' ability to bind to TPP1 and therefore to confirm our abilities to identify bindable drugs through docking. From this work we are hopeful we will be able to identify FDA approved and BBB-crossing drugs that can selectively bind to TPP1 and restore enough function to avoid cell death. This discovery could lead to a treatment of CLN2 disease that does not involve the current invasive intraventricular infusions currently required.