ArticleACS chemical neuroscience2023
Doubly Constrained C-terminal of Roc (COR) Domain-Derived Peptides Inhibit Leucine-Rich Repeat Kinase 2 (LRRK2) Dimerization.
Article in ACS chemical neuroscience, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 21 citations in OpenAlex.
- Constrained peptide mimics of the LRRK2 C-terminal Helix inhibits its kinase activity.Bioorganic chemistry · 2026Article
- Gaps in the Parkinson's disease therapeutic clinical pipeline: A focus on approaches targeting disease pathobiology.Journal of Parkinson's disease · 2026Review
- Mechanistic design of cell-penetrating disruptors for phospho-dependent TACC3-CHC interaction.Structure (London, England : 1993) · 2026Article
- Regulation between LRRK2 and PP2A signaling in cellular models of Parkinson's disease.The Biochemical journal · 2026Article
- Pathological Protein Targets in Parkinson's Disease: Progress Towards the Development of Disease-Modifying Therapies.CNS drugs · 2026Review
- Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.eLife · 2024Article
- LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.Trends in molecular medicine · 2024Review
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- Article
- A critical evaluation of protein kinase regulation by activation loop autophosphorylation.eLife · 2023Article
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Authors and funding
14 authors at 4 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Missense mutations along the leucine-rich repeat kinase 2 (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 peptide inhibitors that target and downregulate LRRK2 activity through disruption of LRRK2 dimerization. In this study, we designed doubly constrained peptides with the objective of inhibiting C-terminal of Roc (COR)-COR mediated dimerization at the LRRK2 dimer interface. We show that the doubly constrained peptides are cell-permeant, bind wild-type and pathogenic LRRK2, inhibit LRRK2 dimerization and kinase activity, and inhibit LRRK2-mediated neuronal apoptosis, and in contrast to ATP-competitive LRRK2 kinase inhibitors, they do not induce the mislocalization of LRRK2 to skein-like structures in cells. This work highlights the significance of COR-mediated dimerization in LRRK2 activity while also highlighting the use of doubly constrained peptides to stabilize discrete secondary structural folds within a peptide sequence.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.