Constrained peptide mimics of the LRRK2 C-terminal Helix inhibits its kinase activity.

“Constrained peptide mimics of the LRRK2 C-terminal Helix inhibits its kinase activity. Chen T(1), Alexander KK(2), Martinez Fiesco JA(3), Naaldijk Y(4), Fasiczka R(4), Brahmia B(4), de la Cruz AA(3), LeClair TJ(2), Steude EG(1), Zhang P(3), Hilfiker S(4), Kennedy EJ(5). Author information: (1)Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. (2)Department of Pharmaceutical and Biomedical Sciences, University of Georgia, College of Pharmacy, Athens, GA 30602, USA. (3)Kinase Complexes Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. (4)Department of Anesthesiology and Department of Physiology, Pharmacology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ 07103, USA. (5)Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: Eileen.Kennedy@unc.edu. Leucine-rich repeat kinase 2 (LRRK2) is the most frequently mutated gene in Parkinson's disease (PD), a neurodegenerative disorder affecting over 10 million people. PD-related pathogenic mutations in LRRK2 increase its kinase activity, thereby contributing to disease pathology. While elevated LRRK2 activity is a recognized contributor to PD, the precise mechanisms by which its various domains regulate kinase activation remain unclear. To address this, we developed hydrocarbon-constrained peptides that mimic the C-terminal helix of LRRK2, a region implicated in modulating its kinase activity. These peptides are cell-penetrant, directly bind LRRK2, and inhibit kinase function. Consequently, they suppress downstream LRRK2-associated pathological phenotypes, including centrosomal and ciliary defects. Unlike many ATP-competitive LRRK2 inhibitors that induce LRRK2 mislocalization, these peptides do not alter LRRK2 localization. Our findings highlight a potentially critical regulatory role of the LRRK2 C-terminal helix and suggest a novel, alternative strategy for modulating pathogenic LRRK2 activity as relevant in PD. Copyright © 2024. Published by Elsevier Inc. Conflict of interest statement: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eileen Kennedy has patent #Allosteric Inhibitors of Leucine Rich Repeat Kinase 2 (LRRK2) pending to UNC Chapel Hill. Tiancheng Chen has patent #Allosteric Inhibitors of Leucine Rich Repeat Kinase 2 (LRRK2) pending to UNC Chapel Hill. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.”