High-throughput screening

A board to discuss future MS therapies in early stage (Phase I or II) trials.

High-throughput screening

Postby dignan » Sun May 20, 2007 3:14 pm

There are many efforts under way to using high-throughput screening technology to assess existing drugs / compounds for potential use to treat MS.



Identifying Druglike Inhibitors of Myelin-Reactive T Cells by Phenotypic High-Throughput Screening of a Small-Molecule Library.

J Biomol Screen. 2007 May 3; [Epub ahead of print]
Rossi C, Padmanaban D, Ni J, Yeh LA, Glicksman MA, Waldner H.
Brigham and Women's Hospital and Harvard Medical School.

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)- gamma 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 Lipinskis 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.

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