Labeling of CC Chemokine Receptor 2 with a Versatile Intracellular Allosteric Probe
Lisa S den Hollander1, Bert L H Beerkens1, Sebastian Dekkers1
1Leiden Academic Centre for Drug Research, Division of Medicinal Chemistry, Leiden 2333 CC, The Netherlands.
ACS Chemical Biology
|August 26, 2024
Summary
Researchers developed novel affinity-based probes (AfBPs) to study G protein-coupled receptors (GPCRs), specifically targeting CCR2. These versatile AfBPs offer a promising alternative to antibodies for drug discovery and target validation.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- G protein-coupled receptors (GPCRs) are crucial drug targets, particularly CCR2 for inflammatory diseases and cancer.
- Traditional tools like antibodies have limitations in studying GPCRs.
- Affinity-based probes (AfBPs) offer a versatile alternative for GPCR interrogation.
Purpose of the Study:
- To develop and validate novel AfBPs targeting the intracellular allosteric pocket of CCR2.
- To assess the utility of these AfBPs in various in vitro experimental settings.
- To establish AfBPs as valuable tools for drug discovery and target validation.
Main Methods:
- Development of AfBPs with a click chemistry handle for two-step labeling.
- Application of AfBPs in SDS-PAGE and LC/MS-based proteomics.
- Validation of probe selectivity, versatility, and applicability.
Main Results:
- Successful development and validation of CCR2-targeting AfBPs.
- Demonstrated utility of AfBPs across multiple detection techniques.
- Probes exhibited high selectivity, versatility, and applicability in vitro.
Conclusions:
- Novel AfBPs provide a valuable alternative to traditional CCR2-targeting antibodies and tool compounds.
- These AfBPs can aid in target validation and engagement within drug discovery pipelines.
- The developed probes enhance the study of GPCRs like CCR2 for therapeutic development.
