A Small-molecule Screen Yields Idiotype-specific Blockers of Neuromyelitis Optica Immunoglobulin G Binding to Aquaporin-4

作者：Phuan Puay Wah; Anderson Marc O; Tradtrantip Lukmanee; Zhang Hua; Tan Joseph; Lam Chiwah; Bennett Jeffrey L; Verkman A S^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287(44): 36837-36844.

DOI：10.1074/jbc.M112.408716

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system caused by binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) to AQP4 on astrocytes. A screen was developed to identify inhibitors of NMO-IgG-dependent, complement-dependent cytotoxicity. Screening of 50,000 synthetic small molecules was done using CHO cells expressing human AQP4 and a human NMO recombinant monoclonal antibody (rAb-53). The screen yielded pyrano[2,3-c]pyrazoles that blocked rAb-53 binding to AQP4 and prevented cytotoxicity in cell culture and spinal cord slice models of NMO. Structure-activity analysis of 82 analogs yielded a blocker with IC50 similar to 6 mu M. Analysis of the blocker mechanism indicated idiotype specificity, as (i) pyrano[2,3-c] pyrazoles did not prevent AQP4 binding or cytotoxicity of other NMO-IgGs, and (ii) surface plasmon resonance showed specific rAb-53 binding. Antibody structure modeling and docking suggested a putative binding site near the complementarity-determining regions. Small molecules with idiotype-specific antibody targeting may be useful as research tools and therapeutics.

• 出版日期2012-10-26