Development of FERM domain protein-protein interaction inhibitors for MSN and CD44 as a potential therapeutic
Yuhong Du1, William J Bradshaw2, Tina M Leisner3
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA; Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Abstract:
Recent genome-wide association studies have revealed genetic risk factors for Alzheimer's disease (AD) that are exclusively expressed in microglia within the brain. A proteomics approach identified moesin (MSN), a FERM (four-point-one ezrin radixin moesin) domain protein, and the receptor CD44 as hub proteins found within a co-expression module strongly linked to AD clinical and pathological traits as well as microglia. The FERM domain of MSN interacts with the phospholipid PIP2 and the cytoplasmic tails of receptors such as CD44. This study explored the feasibility of developing protein-protein interaction inhibitors that target the MSN-CD44 interaction. Structural and mutational analyses revealed that the FERM domain of MSN binds to CD44 by incorporating a beta strand within the F3 lobe. Phage-display studies identified an allosteric site located close to the PIP2 binding site in the FERM domain that affects CD44 binding within the F3 lobe. These findings support a model in which PIP2 binding to the FERM domain stimulates receptor tail binding through an allosteric mechanism that causes the F3 lobe to adopt an open conformation permissive for binding. High-throughput screening of a chemical library identified two compounds that disrupt the MSN-CD44 interaction, and one compound series was further optimized for biochemical activity, specificity, and solubility. The results suggest that the FERM domain holds potential as a drug development target. The small molecule preliminary leads generated from the study could serve as a foundation for additional medicinal chemistry effort with the goal of controlling microglial activity in AD by modifying the MSN-CD44 interaction.
Insights
Researchers identified potential drug targets by studying the moesin-CD44 interaction in microglia, crucial for Alzheimer's disease (AD) risk. Small molecules were developed to disrupt this interaction, offering a new avenue for AD treatment.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Genetic risk factors for Alzheimer's disease (AD) are linked to microglial gene expression.
- Moesin (MSN) and CD44 are identified as key proteins in microglial co-expression modules associated with AD pathology.
Approach:
- Investigated the structural basis of the moesin FERM domain interaction with CD44.
- Utilized phage display to identify allosteric sites on MSN affecting CD44 binding.
- Screened a chemical library to find compounds inhibiting the MSN-CD44 interaction.
Key Points:
- The moesin FERM domain binds CD44 via a beta strand in the F3 lobe.
- An allosteric site near the PIP2 binding site modulates CD44 interaction.
- PIP2 binding to MSN's FERM domain promotes CD44 binding through an allosteric mechanism.
Conclusions:
- The moesin FERM domain is a potential drug development target for Alzheimer's disease.
- Identified preliminary small molecule leads that disrupt the moesin-CD44 interaction.
- These leads could form the basis for therapies modulating microglial activity in AD.
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