Figure 1: Diagram of pHLIP Transmembrane Insertion.

pHLIP can exist in three states: unstructured in solution (State 1) (not shown), docked at a cell membrane but not inserted (State 2) (left), and inserted across a cell membrane as a transmembrane alpha helix (State 3) (right). At normal physiologic pH, pHLIP exists in an equilibrium between States 1 and 2. At acidic pH, State 2 pHLIP adopts an alpha helical conformation and then transitions to State 3 via transmembrane insertion. A cargo molecule can be attached to the inserting end of pHLIP via a disulfide bond, which, after transmembrane insertion, is reduced in the cell cytoplasm, thereby releasing the cargo molecule.