Getting bifunctional molecules into cells

Description A class of transmembrane proteins helps shuttle large drugs across the cell membrane Simultaneously optimizing biochemical potency and membrane permeability remains one of the biggest challenges in drug development. For typical drug targets, such as enzymes and receptors, finding a configuration of atoms that will allow target binding with high affinity can be relatively easy to achieve using drug-like molecules, which are generally below ∼600 Da. However, there is a long list of therapeutically compelling targets inside the cell that either lack the kinds of deep pockets appropriate for binding drug-like small molecules or have multiple pockets separated over large distances. For molecules that are large enough to effectively engage challenging protein interfaces, getting past the cell membrane can be insurmountable. On page 1097 of this issue, Lou et al. (1) describe a mechanism by which large, dumbbell-shaped (bitopic) molecules with molecular weights as high as 1784 Da can access the cytoplasm, revealing a potential avenue to reach intractable intracellular targets.