New, more sensitive sensor for evaluating drug safety

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A new technique for evaluating drug safety can detect stress on cells at earlier stages than conventional methods, which mostly rely on detecting cell death. The new method uses a fluorescent sensor that is turned on in a cell when misfolded proteins begin to aggregate -- an early sign of cellular stress. The method can be adapted to detect protein aggregates caused by other toxins as well as diseases such as Alzheimer’s or Parkinson’s. A paper describing the new method, by a team of researchers at Penn State University, appears in the journal Angewandte Chemie International Edition.

A new technique for evaluating drug safety can detect stress on cells at earlier stages than conventional methods, which mostly rely on detecting cell death. The new method uses a fluorescent sensor that is turned on in a cell when misfolded proteins begin to aggregate -- an early sign of cellular stress. The method can be adapted to detect protein aggregates caused by other toxins as well as diseases such as Alzheimer’s or Parkinson’s. A paper describing the new method, by a team of researchers at Penn State University, appears in the journal Angewandte Chemie International Edition.

“Drug-induced protein stress in cells is a key factor in determining drug safety,” said Xin Zhang, assistant professor of chemistry and of biochemistry and molecular biology at Penn State, the senior author of the paper. “Drugs can cause proteins -- which are long strings of amino acids that need to be precisely folded to function properly -- to misfold and clump together into aggregates that can eventually kill the cell. We set out to develop a system that can detect these aggregates at very early stages and that also uses technology that is affordable and accessible to many laboratories.”

The new system is the first to use a fluorescent sensor that is not turned on until the misfolded proteins begin to aggregate. The researchers designed an unstable protein -- called AgHalo -- that is tagged with a special fluorescent dye that becomes active in a hydrophobic, i.e. water-repellent, environment. Hydrophobic portions of proteins are usually buried deep in the structure of a properly-folded protein because the environment of the cell is mostly water. When the AgHalo protein begins to misfold and aggregate the dye can interact with the hydrophobic portions of the protein and begin to fluoresce.

Read more at Penn State

Image: Image of cells expressing the AgHalo sensor before (left) and after (right) cellular stress. The AgHalo sensor is turned on when misfolded proteins begin to aggregate and provides a quantitative measure of cellular stress that can be used to evaluate drug safety. (Credit: Yu Liu, Penn State University)