Abstract
A series of 16 synthetic scramblase candidates were prepared from a tris(aminoethyl)amine (TREN) scaffold and evaluated for ability to facilitate translocation of fluorescent phospholipid probes across vesicle membranes and endogenous phosphatidylserine across the plasma membrane of nucleated cells. More than half of the compounds were found to greatly accelerate phospholipid translocation in vesicles. However, they were generally unable to induce large increases in the amount of phosphatidylserine on the surface of nucleated mammalian cells, which contrasts with previous results using erythrocytes. Fluorescence microscopy showed that the synthetic scramblases are rapidly trafficked out of the cell plasma membrane and into the membranes of internal organelles. Future molecular designs of synthetic scramblases should focus on structures that are more amphiphilic, a structural feature that is expected to increase plasma membrane residence time.