New Method May Detect Drug’s Toxic Side Effects Early in Development
Scientists at Weill Cornell Medical College say they have devised a new drug screen that capitalizes on the tendency of toxic compounds to alter the properties of the lipid bilayer that encases cells. The novel screen, called the Gramicidin-Based Fluorescence Assay (GBFA), repurposes an assay previously developed by principal investigator Olaf Andersen, M.D., and a former graduate student Helgi Ingólfsson. It tracks changes in the activity of a small protein (the gramicidin channel) coupled to a fluorescence signal as a way of monitoring changes in lipid bilayer properties, a correlate for toxicity.The researchers presented a paper (“Predicting Ddrug Toxicity: Early Detection of Likely Failures in Drug Development”) on their screening method yesterday at the Biophysical Society Conference in Baltimore.Changes to the properties of the lipid bilayer component of the cell membrane can alter the function of proteins embedded in the membrane: proteins that regulate critical functions such as transport of materials in and out of the cell and communication with other cells.“As we gathered data, we began to notice a trend: molecules that significantly affected lipid bilayer properties were often indiscriminate modifiers of membrane protein function and thus tended to have an array of off-target effects,” said researcher Lea Sanford. That is, when compounds intended to influence a specific protein target also alter lipid bilayer properties, they may alter the function of numerous membrane proteins and thereby cause a cascade of usually unwanted off-target and side effects.