A small-molecule screen yields idiotype-specific blockers of neuromyelitis optica immunoglobulin G binding to aquaporin-4

Abstract

Background: A high-throughput cytotoxicity-based screen was developed to identify small-molecule inhibitors of NMO-IgGAQP4 binding. Results: Pyrano[2,3-c]pyrazoles were identified as inhibitors and were shown to bind directly to theNMOmonoclonal antibody used for screening but did not interfere with other NMO-IgGs that bound to AQP4. Conclusion: Pyrano[2,3-c]pyrazoles are idiotype-specific to the NMO recombinant monoclonal antibody used for screening. Significance: Our results establish a proof of concept for an antibody-targeted small-molecule blocker strategy to prevent specific antibody-antigen binding. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.