A Small-molecule Screen Yields Idiotype-specific Blockers of Neuromyelitis Optica Immunoglobulin G Binding to Aquaporin-4
Year: 2012
Type: article
Abstract: 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 IC(50) ∼ 6 μm. 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.
Source: Journal of Biological Chemistry
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: G1259071441, Role of airway submucosal glands in CF lung disease, Application of Novel Optical Methods to Cell Dynamics, G3011728751, G3102004739, Application of Novel Optical Methods to Cell Dynamics, Aquaporin-4 in NMO Optic Neuritis: Pathogenesis and New Therapies, G3699204242, G3730553470, Mechanisms of water transport in renal epithelia, G4468004498, MECHANISMS OF WATER TRANSPORT IN RENAL EPITHELIA, CFTR inhibitors for therapy of polycystic kidney disease, Novel small-molecule therapies for CF
OpenAlex ID: W2083434189