Cell-penetrating peptides and antimicrobial peptides: how different are they?

Abstract

Some cationic peptides, referred to as CPPs (cell-penetrating peptides), have the ability to translocate across biological membranes in a non-disruptive way and to overcome the impermeable nature of the cell membrane. They have been successfully used for drug delivery into mammalian cells; however, there is no consensus about the mechanism of cellular uptake. Both endocytic and non-endocytic pathways are supported by experimental evidence. The observation that some AMPs (antimicrobial peptides) can enter host cells without damaging their cytoplasmic membrane, as well as kill pathogenic agents, has also attracted attention. The capacity to translocate across the cell membrane has been reported for some of these AMPs. Like CPPs, AMPs are short and cationic sequences with a high affinity for membranes. Similarities between CPPs and AMPs prompted us to question if these two classes of peptides really belong to unrelated families. In this Review, a critical comparison of the mechanisms that underlie cellular uptake is undertaken. A reflection and a new perspective about CPPs and AMPs are presented.

Figure 1. CPP translocation by a physically driven process can be regarded as a composite of three sequential steps

(A) The peptide (dark-grey cylinder) inserts in the bilayer outer interface (light-grey head-groups with fatty acid tails) and causes local membrane perturbation. (B) Owing to a membrane gradient (e.g. transmembrane potential, pH gradient) or concentration effects, the peptide overcomes the hydrophobic core of the bilayer by an unknown mechanism. (C) The peptide is released from the inner leaflet of the membrane (blue head-groups with fatty acid tails) to the cytoplasm. In a model artificial system (e.g. a vesicle) the system would tend to an equilibrium that can be accounted for by three different partition constants, one for each of the elementary steps (A, B and C).