Small Molecule Inhibitors of the CRMP2-CaV2.2 Voltage-gated Calcium Channel Interaction to Find New Treatments for Pain

National Center For Advancing Translational Sciences

Investigators

Abstract

Based on the collaborators' hypothesis, the NCATS biology team developed three novel assays to examine key aspects of the working model. These assays include: 1) the CRMP2-CaV2.2 HiBiT protein-protein interaction assay, which utilizes HiBiT technology to assess the interaction between binding partners after compound treatment; 2) the high-throughput CaV2.2 membrane localization assay, designed to evaluate the surface expression of the channel; and 3) the CaV2.2 FLIPR assay, which analyzes calcium influx mediated by CaV2.2. The CaV2.2 FLIPR assay is ready to use, and the development of other assays is currently underway. The team will utilize these assays to evaluate the prior art and make a go/no-go decision for this project based on the team’s consensus. The goals of this project are as follows: establish and optimize quantitative high-throughput screening (qHTS) methods and orthogonal assays to develop small-molecule modulators of the Cav2.2 voltage-gated calcium channel; and develop small molecules targeting the CRMP2-Cav2.2 voltage-gated calcium channel interaction and validate them as potential safer pain treatments.