Optical probe IDs protein binding site for improved Alzheimer's research

When the probe is illuminated, it catalyzes oxidation of the protein in a way that might keep it from aggregating in the brains of patients.

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Researchers at Rice University (Houston, TX) have developed a probe that lights up when it binds to a misfolded amyloid beta peptide—the kind suspected of causing Alzheimer's disease. The probe has identified a specific binding site on the protein that could facilitate better drugs to treat the disease. The researchers also discovered that when the metallic probe is illuminated, it catalyzes oxidation of the protein in a way they believe might keep it from aggregating in the brains of patients.

Related: Optical imaging method maps Alzheimer's protein deposits in 3D

The study done on long amyloid fibrils backs up computer simulations by colleagues at the University of Miami (Coral Gables, FL) that predicted the photoluminescent metal complex would attach itself to the amyloid peptide near a hydrophobic (water-avoiding) cleft that appears on the surface of the fibril aggregate. That cleft presents a new target for drugs.

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A rhenium-based complex developed at Rice University binds to fibrils of misfolded amyloid beta peptide, which marks the location of a hydrophobic cleft that could serve as a drug target, and oxidizes the fibril, which changes its chemistry in a way that could prevent further aggregation. (Courtesy of the Martí Group)

Finding the site was relatively simple once the lab of Rice chemist Angel Martí used its rhenium-based complexes to target fibrils. The light-switching complex glows when hit with ultraviolet light, but when it binds to the fibril, it becomes more than 100X brighter and causes oxidation of the amyloid peptide.

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A metallic probe lights up when it binds to a misfolded amyloid beta peptide in an experiment at Rice University. The probe identified a binding site that could facilitate better drugs to treat Alzheimer’s disease. (Photo by Brandon Martin)

"We believe this hydrophobic cleft is a general binding site (on amyloid beta) for molecules," Martí says. "This is important because amyloid beta aggregation has been associated with the onset of Alzheimer's disease. We know that fibrillar insoluble amyloid beta is toxic to cell cultures. Soluble amyloid oligomers that are made of several misfolded units of amyloid beta are also toxic to cells, probably even more than fibrillar."

"There's an interest in finding medications that will quench the deleterious effects of amyloid beta aggregates," Martí says. "But to create drugs for these, we first need to know how drugs or molecules in general can bind and interact with these fibrils, and this was not well known. Now we have a better idea of what the molecule needs to interact with these fibrils."

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(L-R) Rice University research scientist Christopher Pennington, graduate student Bo Jiang, and Angel Martí, an associate professor of chemistry and bioengineering, run an amyloid beta experiment in the Martí lab. (Photo by Brandon Martin)

When amyloid peptides fold properly, they hide their hydrophobic residues while exposing their hydrophilic (water-attracting) residues to water. That makes the proteins soluble, Martí says. But when amyloid beta misfolds, it leaves two hydrophobic residues, known as Valine 18 and Phenylalanine 20, exposed to create the hydrophobic cleft.

If the resulting oxidation keeps the fibrils from aggregating farther into the sticky substance found in the brains of Alzheimer's patients, it may be the start of a useful strategy to stop aggregation before symptoms of the disease appear.

Martí says that if the complexes can be modified so they absorb red light (which is transparent to tissue), they may be able to perform these photochemical modifications in living animals, and maybe someday in humans.

Full details of the work appear in the journal Chem.

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