Sequestering Cholera

A PEPTIDE MIMIC attached to a polymer bead selectively grabs hold of cholera toxin and protects gut cells from cholera's deadly effects. This type of molecule could inspire new therapies for cholera and other diarrheal diseases.

Without the right treatment, bacterial toxin-mediated diarrheal disease can be fatal. Patients typically receive fluids and antibiotics, but because antibiotic resistance is on the rise, researchers are seeking complementary therapies. Polymeric particles that sequester toxins in the gut, from which they can then be passed through the stool, are an appealing option.

Such polymers tend not to be selective for their targets, however, and none have been approved by FDA for fighting diarrhea-causing bacteria. Lyle Burdine, an M.D./Ph.D. candidate at the University of Texas Southwestern Medical Center (UTSW), dreamed up the idea for a next-generation binder, says biochemist Thomas J. Kodadek, who led the UTSW team that realized the dream. "Lyle's vision was, 'Why not develop a selective binding agent for a toxin on a polymer support?' " Kodadek says. Selectivity, the team surmised, might lead to a more effective treatment.

Burdine, Kodadek, and postdoctoral fellow Levi S. Simpson identified a selective, tight-binding ligand motif for cholera toxin by screening bead-bound libraries of peptide mimics called peptoids (J. Am. Chem. Soc., DOI: 10.1021/ja900852k). Individual peptoid hits interacted weakly with individual toxin subunits, Kodadek notes. But cholera has a five-subunit toxin, so the cooperative binding action of several peptoids makes for a tight interaction, much like how Velcro works, he adds.

"The relative ease of peptoid synthesis, their compatibility with solid-phase techniques, and stability in the body suggests this could be a far-ranging approach," comments Helen E. Blackwell, a peptoid expert at the University of Wisconsin, Madison.

In collaboration with Andrew P. Feranchak, an expert in gut physiology at UTSW, Kodadek's team used a peptoid to defend human intestinal cells in culture from the electrolyte-depleting effects of cholera toxin. In the future, they hope to optimize the peptoids for animal tests and adapt them to target other toxins.