Cell-penetrating peptides: classes, origin, and current landscape

With more than ten new FDA approvals since 2001, peptides are emerging as an important therapeutic alternative to small molecules. However, unlike small molecules, peptides on the market today are limited to extracellular targets. By contrast, cell-penetrating peptides (CPPs) can target intracellular proteins and also carry other cargoes (e.g. other peptides, small molecules or proteins) into the cell, thus offering great potential as future therapeutics. In this review I present a classification scheme for CPPs based on their physical–chemical properties and origin, and I provide a general framework for understanding and discovering new CPPs.

► More than 100 CPPs are presented, divided into cationic, amphipathic, and hydrophobic. ► Origin-based classification: natural proteins/peptides; designed; random libraries ► Natural sources of CPPs: heparin-, DNA/RNA binding proteins; viral proteins; antimicrobial/signal peptides.