Exploring novel ways to target LRRK2 in Parkinson’s disease: in-depth characterization and optimization of allosteric Nanobodies

Parkinson’s disease (PD) affects millions worldwide and is still without a cure. Mutations in the gene encoding Leucine-Rich Repeat Kinase 2 (LRRK2) are the most common cause of familial PD, while the upregulation of LRRK2 activity is also associated with the more frequent idiopathic form of the disease. As a result, LRRK2 is regarded as one of the most promising targets for PD drug development. Currently available kinase inhibitors have been associated with potential toxic side
effects, necessitating the search for alternative methods to target LRRK2. We recently identified Nanobodies (Nbs) acting as allosteric inhibitors of LRRK2, with a mechanism of action that differs from known kinase inhibitors. The current project aims to characterize and optimize these Nbs, paving the way for their application in novel therapeutic approaches for treating PD. A full biochemical and structural characterization of the Nbs will yield a thorough understanding of their mode of action. Additionally, structures of LRRK2 in complex with inhibitory Nbs will reveal allosteric pockets for the development of innovative small-molecule inhibitors. Finally, several engineering approaches will be employed to tailor and optimize these Nbs for various therapeutic applications, as well as for diagnostic and imaging purposes.