Doubly Constrained C-terminal of Roc (COR) Domain-Derived Peptides Inhibit Leucine-Rich Repeat Kinase 2 (LRRK2) Dimerization

Missense mutations along the leucine-rich repeat kinase2 (LRRK2)protein are a major contributor to Parkinson's Disease (PD),the second most commonly occurring neurodegenerative disorder worldwide.We recently reported the development of allosteric constrained peptideinhibitors that target and downregulate LRRK2 activity through disruptionof LRRK2 dimerization. In this study, we designed doubly constrainedpeptides with the objective of inhibiting C-terminal of Roc (COR)-CORmediated dimerization at the LRRK2 dimer interface. We show that thedoubly constrained peptides are cell-permeant, bind wild-type andpathogenic LRRK2, inhibit LRRK2 dimerization and kinase activity,and inhibit LRRK2-mediated neuronal apoptosis, and in contrast toATP-competitive LRRK2 kinase inhibitors, they do not induce the mislocalizationof LRRK2 to skein-like structures in cells. This work highlights thesignificance of COR-mediated dimerization in LRRK2 activity whilealso highlighting the use of doubly constrained peptides to stabilizediscrete secondary structural folds within a peptide sequence.