Allosteric inhibition of LRRK2, where are we now

Soliman, Ahmed; Çankara, Fatma Nihan; Kortholt, Arjan

doi:10.1042/bst20200424

Cited by 13 publications

(13 citation statements)

References 86 publications

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“…The first Roc domain-targeting, GTP-competitive inhibitors have been developed. To identify new targeting surfaces and further develop these sorts of compounds for allosteric targeting of LRRK2 [130], further characterization of the LRRK2 activation mechanism and high-resolution structures will be of great importance. In this respect, the recently identified full-length structure of LRRK2 will be instrumental [31].…”

Section: Discussionmentioning

confidence: 99%

LRRK2 Targeting Strategies as Potential Treatment of Parkinson’s Disease

Wojewska

Kortholt

2021

Biomolecules

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Parkinson’s Disease (PD) affects millions of people worldwide with no cure to halt the progress of the disease. Leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of PD and, as such, LRRK2 inhibitors are promising therapeutic agents. In the last decade, great progress in the LRRK2 field has been made. This review provides a comprehensive overview of the current state of the art, presenting recent developments and challenges in developing LRRK2 inhibitors, and discussing extensively the potential targeting strategies from the protein perspective. As currently there are three LRRK2-targeting agents in clinical trials, more developments are predicted in the upcoming years.

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Section: Discussionmentioning

confidence: 99%

LRRK2 Targeting Strategies as Potential Treatment of Parkinson’s Disease

Wojewska

Kortholt

2021

Biomolecules

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“…Indeed, small molecule LRRK2 kinase inhibitors, as well as an antisense LRRK2 oligo, are currently in clinical trials for PD indications [ 90 ]. In addition, other types of inhibitors have been developed, either targeting the G-protein cycle by inhibiting its GTPase activity or by inhibiting LRRK2's protein–protein interactions (such as with 14-3-3) [ 91 ]. The proliferation in LRRK2 inhibitor development highlights that pharmacologically targeting LRRK2 could be a highly potent solution to diminish pathogenic LRRK2 effects.…”

Section: Lrrk2 and Basal Mitophagymentioning

confidence: 99%

Parkinson's disease and mitophagy: an emerging role for LRRK2

Singh

Ganley

2021

Biochemical Society Transactions

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Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress — so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

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“…To date, efforts to allosterically inhibit LRRK2 are limited due to the complex nature of characterizing protein–protein interactions and difficulty in targeting these interfaces with traditional small molecules. [ 89 ] Recently, cell penetrating peptides were designed to effectively disrupt the interaction between LRRK2 and protein phosphatase 1 (PP1), which dephosphorylates LRRK2. [ 90 ] Initial work determined that these peptides were able to permeate cells, resist proteolytic degradation, and block the interaction between LRRK2 and PP1.…”

Section: Protein–protein Interactions Driving Lrrk2 Regulationmentioning

confidence: 99%

Leucine rich repeat kinase 2 (LRRK2) peptide modulators: Recent advances and future directions

et al. 2021

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Leucine rich repeat kinase 2 (LRRK2) is the most common genetic contributor to Parkinson's disease (PD), a complex neurodegenerative disorder affecting nearly 10 million people worldwide. Pathogenic mutations within LRRK2 often induce increased kinase activity, an effect that can be abolished with many small molecule inhibitors; however, these small molecule inhibitors are currently limited by their toxicities. Given the large and complex nature of LRRK2, more recent efforts have focused on protein–protein interactions (PPIs) involving LRRK2 and how they can contribute to PD. Here, we review recently resolved structures of LRRK2 and highlight unique interfaces driving both catalytic and non‐catalytic activities. Combining new structural information with established in vitro and in vivo data clarifies the role of PPIs in driving LRRK2‐mediated disease pathogenesis. Since constrained peptides and peptidomimetics have the potential to engage with elongated, hydrophobic interfaces that were previously considered “undruggable,” they may provide a unique handle for LRRK2 targeting. Here, we discuss the use of constrained peptides and peptidomimetics to target LRRK2 as a strategy to downregulate its pathological activity.

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Allosteric inhibition of LRRK2, where are we now

Cited by 13 publications

References 86 publications

LRRK2 Targeting Strategies as Potential Treatment of Parkinson’s Disease

LRRK2 Targeting Strategies as Potential Treatment of Parkinson’s Disease

Parkinson's disease and mitophagy: an emerging role for LRRK2

Leucine rich repeat kinase 2 (LRRK2) peptide modulators: Recent advances and future directions

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