Screen Nets Self-Destruction Stoppers | December 7, 2009 Issue - Vol. 87 Issue 49 | Chemical & Engineering News
Volume 87 Issue 49 | p. 8 | News of The Week
Issue Date: December 7, 2009

Screen Nets Self-Destruction Stoppers

Chemical Biology: Strategy finds selective ligands for rogue T cells
Department: Science & Technology
Keywords: peptoid, multiple sclerosis, high-throughput screen

With a new screening process, researchers have found small molecules that specifically bind to the surface of a mouse's autoreactive T cells, a kind of immune cell that attacks its host. The work could pave the way for new treatments for multiple sclerosis (MS) or other conditions in which autoreactive T cells run amok.

Most marketed drugs for treating autoimmune diseases nonselectively adjust immune system function, which can lead to flulike side effects. Searches for more selective agents have focused on finding out what triggers the autoreactive T cells, but these approaches have been slow to bear fruit, says Thomas Kodadek of Scripps Florida.

Now, Kodadek and coworkers have developed a screen that doesn't require that information. They begin with T-cell samples taken from mice with an MS-like condition. The team then isolates autoreactive T cells from the samples and uses them to search for specific binders in a library of synthetic peptoids, which are peptide mimics.

The researchers found two peptoids that recognize autoreactive T cells while bypassing other, non-disease-causing T cells (Chem. Biol., DOI: 10.1016/j.chembiol.2009.10.011). Prior to Kodadek's work, no other small molecules had shown an ability to bind to rare T cells that drive autoimmune disorders, says Garry P. Nolan, who studies autoimmunity at Stanford University.

One of the team's peptoids, called AG12A, helps halt the development of MS in mice. Normally, injecting a specific sample of autoreactive T cells into healthy mice gives the rodents MS. But treating the cells with AG12A modified with a photoreactive group, and injecting them into mice caused no sickness. The team suggests that AG12A steers the light-reactive warhead; a control peptoid conjugate didn't shield the mice from MS.

The targets for autoimmune cells could differ among individuals suffering from the same disease, comments David A. Spiegel, who synthesizes small-molecule immune modulators at Yale University. "Kodadek's ingenious approach doesn't require knowledge about particular targets, so it could someday lead to more personalized treatments," he says.

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