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Allosteric targeting of LRRK2 using stapled peptides

This grant builds upon the research from a prior grant: From Structure to Function: Targeting LRRK2-mediated Parkinson's Disease

Study Rationale:
Mutations in the LRRK2 gene -- which alter enzymatic activity in the LRRK2 protein -- are associated with increased risk of Parkinson's disease. The protein is known to aggregate into small forms called dimers, but we don't fully understand how its activity is regulated and how mutations alter the protein's activity. To study this, we will develop disruptors that block LRRK2 dimerization and examine its regulatory mechanism.

We will explore the hypothesis that blocking LRRK2 dimerization may serve as an effective strategy to decrease activity of LRRK2 function, reducing its damaging effects in the brain.

Study Design:
We will design compounds to mimic portions of the LRRK2 protein that are involved in dimerization. These compounds will be tested using purified proteins to determine whether they can block dimer formation and inhibit LRRK2 activity within a cellular environment. Based on these findings, we will optimize the compounds to enhance affinity, target specificity and efficacy.

Impact on Diagnosis/Treatment of Parkinson's disease:
These compounds could become the first LRRK2 inhibitors that specifically target dimerization. This study could validate dimerization disruption as a novel strategy for the treatment of Parkinson's disease.

Next Steps for Development:
The inhibitors developed in this study will validate whether dimerization serves as a good target for LRRK2 inhibitors. The optimized compounds may also serve as templates for developing novel drugs for Parkinson's. Future pre-clinical studies could establish the efficacy and feasibility of this approach.


  • Arjan Kortholt, PhD

    Groningen Netherlands

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