Mechanism Matters: A Taxonomy of Cell Penetrating Peptides

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 40; no. 12; pp. 749 - 764
• Main Authors: Kauffman, W. Berkeley, Fuselier, Taylor, He, Jing, Wimley, William C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2015
• Subjects: Animals; Cell Membrane - chemistry; Cell Membrane - metabolism; cell penetrating peptide (CPP); Cell-Penetrating Peptides - chemistry; Cell-Penetrating Peptides - classification; Cell-Penetrating Peptides - metabolism; cytosolic delivery; Humans; membrane translocation; transient permeabilization; cell penetrating peptide (CPP); cytosolic delivery; membrane translocation; transient permeabilization
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2015.10.004

The permeability barrier imposed by cellular membranes limits the access of exogenous compounds to the interior of cells. Researchers and patients alike would benefit from efficient methods for intracellular delivery of a wide range of membrane-impermeant molecules, including biochemically active small molecules, imaging agents, peptides, peptide nucleic acids, proteins, RNA, DNA, and nanoparticles. There has been a sustained effort to exploit cell penetrating peptides (CPPs) for the delivery of such useful cargoes in vitro and in vivo because of their biocompatibility, ease of synthesis, and controllable physical chemistry. Here, we discuss the many mechanisms by which CPPs can function, and describe a taxonomy of mechanisms that could be help organize future efforts in the field. The functional sequence space for cell penetrating peptides (CPPs) is vast. Recent data from computational, synthetic, and biological systems show that the mechanisms by which they bypass membranes are similarly diverse. The CPP mechanism is mutable; it is not determined by the peptide sequence only. Many other experimental and biological factors are important, including local peptide concentration, local lipid composition, and the properties of the cargo. The position of a CPP within the mechanistic taxonomy, under one set of conditions, can be described by the degree to which it is taken up by endocytosis, and the degree to which it can disrupt membranes. Transformation from a peptide-centric approach to a mechanistic and cargo-centric approach may enable the CPP field to fulfill its long-held promise.