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Small‐molecule inhibitors of NMO‐IgG binding to aquaporin‐4 reduce astrocyte cytotoxicity in neuromyelitis optica
Author(s) -
Tradtrantip Lukmanee,
Zhang Hua,
Anderson Marc O.,
Saadoun Samira,
Phuan PuayWah,
Papadopoulos Marios C.,
Bennett Jeffrey L.,
Verkman A. S.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-201608
Subject(s) - neuromyelitis optica , cytotoxicity , aquaporin 4 , chemistry , autoantibody , astrocyte , microbiology and biotechnology , pharmacology , immunology , antibody , medicine , biochemistry , in vitro , biology , central nervous system
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of spinal cord and optic nerve caused by pathogenic autoantibodies (NMO‐IgG) against astrocyte aquaporin‐4 (AQP4). We developed a high‐throughput screen to identify blockers of NMO‐IgG binding to human AQP4 using a human recombinant monoclonal NMO‐IgG and transfected Fisher rat thyroid cells stably expressing human M23‐AQP4. Screening of ~60,000 compounds yielded the antiviral arbidol, the flavonoid tamarixetin, and several plant‐derived berbamine alkaloids, each of which blocked NMO‐IgG binding to AQP4 without affecting AQP4 expression, array assembly, or water permeability. The compounds inhibited NMO‐IgG binding to AQP4 in NMO patient sera and blocked NMO‐IgG‐dependent complement‐ and cell‐mediated cytotoxicity with IC 50 down to ~5 μM. Docking computations identified putative sites of blocker binding at the extracellular surface of AQP4. The blockers did not affect complement‐dependent cytotoxicity caused by anti‐GD3 antibody binding to ganglioside GD3. The blockers reduced by >80% the severity of NMO lesions in an ex vivo spinal cord slice culture model of NMO and in mice in vivo. Our results provide proof of concept for a small‐molecule blocker strategy to reduce NMO pathology. Small‐molecule blockers may also be useful for other autoimmune diseases caused by binding of pathogenic autoantibodies to defined targets.—Tradtrantip, L., Zhang, H., Anderson, M. O., Saadoun, S., Phuan, P.‐W., Papadopoulos, M. C., Bennett, J. L., Verkman, A. S. Small‐molecule inhibitors of NMO‐IgG binding to aquaporin‐4 reduce astrocyte cytotoxicity in neuromyelitis optica. FASEB J. 26, 2197‐2208 (2012). www.fasebj.org