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Identifying Druglike Inhibitors of Myelin-Reactive T Cells by Phenotypic High-Throughput Screening of a Small-Molecule LibraryCenter for Neurologic Diseases, Brigham and Women's Hospital, and Harvard Medical School, Cambridge, Massachusetts
Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital, Cambridge, Massachusetts
Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital, Cambridge, Massachusetts
Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital, Cambridge, Massachusetts, North Carolina Central University, Durham
Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital, Cambridge, Massachusetts
Center for Neurologic Diseases Brigham and Women's Hospital and Harvard Medical School Cambridge, MA 02139, hwaldner{at}rics.bwh.harvard.edu
Inflammatory T cells that are reactive to myelin protein components of the CNS play a critical role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). The authors have previously generated mice that predominantly harbor T cells transgenic for a T-cell receptor (TCR) that is specific to the myelin proteolipid protein (PLP) 139-151 and that spontaneously develop MS-like paralysis. T cells from healthy transgenic mice respond to stimulation with PLP139-151 in a highly specific manner by proliferation and secretion of proinflammatory cytokines such as interleukin (IL)—2 and interferon (INF)—
Key Words: phenotypic high-throughput screening • small-molecule inhibitors • T cells • EAE • multiple sclerosis
This version was published on June
1, 2007 Journal of Biomolecular Screening, Vol. 12, No. 4,
481-489 (2007) |
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in vitro. To identify druglike compounds that may inhibit inflammatory T-cell responses, the authors have developed a high-throughput screening assay with primary T cells from PLP TCR transgenic mice. They have screened 41,184 small-molecule compounds that follow Lipinski's rules for their inhibitory activity on the proliferation and secretion of proinflammatory cytokines in PLP-reactive T cells. To this end, the screen identified 6 nontoxic compounds with a molecular weight <500 that inhibited inflammatory responses in PLP-reactive T cells in a concentration-dependent fashion. The identified compounds represent valid leads that may be developed into novel therapeutics for MS that could be administered orally. (Journal of Biomolecular Screening 2007:481-489)