Cell-Penetrating Peptide (CPP)

A cell-penetrating peptide is a short sequence, usually 5 to 30 residues, that crosses a cell membrane carrying a covalently attached cargo. Most are strongly cationic, built from arginine and lysine, or amphipathic; the archetypes are TAT, a segment of the HIV-1 Tat protein with the core GRKKRRQRRR, and penetratin from the Antennapedia homeodomain. Uptake is mostly by endocytosis, and the cargo then has to escape the endosome, which most of it never does.

In a written sequence the tag is simply a run of arginines and lysines at one end of the block, often behind a short linker. NVG-291, a peptide mimetic of the PTP-sigma wedge domain in early clinical testing for spinal cord injury, carries a TAT segment, and FOXO4-DRI carries a retro-inverso TAT built from D-residues, which appears as a lowercase run of r and k. The class has produced many laboratory tools and few medicines.

What a CPP buys is entry into cells for a cargo that could not otherwise get there, at the cost of entering every cell type indiscriminately. It does not change what happens before the peptide reaches a cell: a TAT-tagged peptide injected subcutaneously is still filtered by the kidney and cut by plasma proteases, and endosomal trapping means the fraction reaching the cytosol is small.

The phrase is routinely stretched. Cell-penetrating is not blood-brain-barrier-penetrating: TAT peptides cross the membranes of cells they touch, and crossing the endothelium into the brain is a separate problem; nor does it mean oral bioavailability or skin penetration. The cationic character that drives uptake also drives membrane disruption at high concentration, so a cell study run at micromolar peptide is not evidence for what happens in a person.