In a recent study conducted by Nick Palmer from Astex Pharmaceuticals, researchers have made significant strides in identifying allosteric-binding site modulators for β-glucocerebrosidase (GBA/ GCase), an enzyme crucial for the treatment of Gaucher’s disease and related neurodegenerative disorders.
This research, titled Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of β‑Glucocerebrosidase, highlights the potential of fragment-based drug discovery (FBDD) and employs permeability assays with CacoReady and PreadyPort plates.
What is GBA in PD and GD?
GBA/ GCase is a lysosomal enzyme that plays a vital role in the hydrolysis of glucosylceramide. Its dysfunction is linked to several serious health conditions, including Gaucher’s disease (GD) and Parkinson’s disease (PD). Mutations in the GBA gene can lead to misfolded protein forms that compromise cellular quality control mechanisms, resulting in the accumulation of toxic substrates.
- Identification of Pharmacological Chaperones: Using fragment-based drug screening (FBDD) to identify compounds that act as pharmacological chaperones has the potential to stabilize misfolded forms of GCase and enhance its activity.
- Modulation of GCase Activity: Researchers aim to find compounds that not only bind to GCase but also positively modulate its activity under cellular conditions. This is crucial to improve the enzyme’s function in patients with mutations that cause its dysfunction.
- Development of Potential Therapies: The goal is to advance the development of new therapies that can be used to treat patients with diseases related to GCase dysfunction, such as Parkinson’s disease.
Utilizing CacoReady and PreadyPort
To evaluate the permeability and absorption characteristics of the newly discovered compounds, the researchers utilized CacoReady and PreadyPort ready-to-use plates:
- CacoReady: This system was essential for assessing the permeability of the compounds across a Caco-2 cell monolayer, which serves as a model for the intestinal barrier. The results indicated promising permeability, suggesting the potential for effective oral therapeutics.
- PreadyPort: The PreadyPort-MDR1 system was employed to further investigate the transport properties of the compounds. This allowed the researchers to evaluate how well the compounds could cross cell membranes and whether they were substrates for efflux transporters like P-glycoprotein.
Promising results
The study revealed that several compounds demonstrated a positive dose-dependent response in enhancing GCase activity in live cell assays. This finding is significant, as it suggests that these compounds could serve as effective treatments for patients with GCase-related disorders.
Read the article here: Palmer et al; “Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of β-Glucocerebrosidase” J Med Chem, 2024 https://doi.org/10.1021/acs.jmedchem.4c00702
