Opening a door into cells

Abstract

The upper size limit on cell-penetrating drug molecules may be much higher than medicinal chemists had thought. A research team reports that molecules believed to be much too large to diffuse across the cell membrane can enter with help from a family of membrane proteins ( Science 2022, DOI: 10.1126/science.abl5829 ). The researchers say the work may open new chemical space for drugging challenging targets. Medicinal chemists use guidelines that consider size, polarity, and other attributes to predict whether a new molecule will behave like a drug. These rules “help you stay in the right sandbox,” says coauthor Kevan Shokat of the University of California, San Francisco. “But sometimes you really need to go outside of that to generate some new functionality.” For example, in 2016, Shokat’s lab designed an unusually large inhibitor of the kinase mTOR, which governs cell growth and is often overactive in cancer. The inhibitor is