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Analytical Chemistry

Bioluminescent Protein Sensors Detect Drugs For Therapeutic Monitoring

Emission at two wavelengths can be measured with a simple digital camera, with the ratio revealing drug concentration

by Celia Henry Arnaud
June 16, 2014 | A version of this story appeared in Volume 92, Issue 24

For many drugs there’s a fine line between efficacy and toxicity, and maintaining the right dose requires close monitoring of the drug concentration. A new family of semisynthetic bioluminescent proteins could bring that monitoring to the patient’s bedside. The sensors, made by Kai Johnsson of ETH Lausanne and coworkers, have three components: a receptor protein that binds the drug of interest, the bioluminescent protein luciferase, and a synthetic portion that contains a ligand for the receptor protein and a cyanine fluorophore (Nat. Chem. Biol. 2014, DOI: 10.1038/nchembio.1554). When the ligand binds the receptor protein, the connection brings the fluorophore close enough to the luciferase to allow bioluminescent resonance energy transfer (BRET) to excite the fluorophore. At sufficient concentrations, the drug of interest displaces the ligand and causes BRET to decrease. The researchers performed the analysis by spotting blood serum on paper and taking a picture with a digital camera. They determined the concentration of the drug from the ratio of the blue light emitted by the luciferase and the red light emitted by the fluorophore. The researchers developed sensors for several drugs, including the anticancer agent methotrexate.

Scheme showing mechanism of drug detection by bioluminescent sensor protein.
Credit: Nat. Chem. Biol.
A drug sensor consists of a receptor protein, luciferase, and a synthetic portion containing a receptor ligand (gray ball) and a fluorophore (red star). In the absence of a drug (green ball), ligand binding pulls the fluorophore close to the luciferase, which transfers bioluminescent energy to the fluorophore through a process known as BRET. The drug displaces the ligand and disrupts the energy transfer. The drug concentration is determined from the ratio of emission from the luciferase and from the fluorophore.

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