Incorporating a β-hairpin sequence motif to increase intracellular stability of a peptide-based PROTAC.

Proteolysis targeting chimeras (PROTACs) have emerged as a new class of therapeutics that utilize the ubiquitin-proteasome system (UPS) to facilitate proteasomal degradation of "undruggable" targets. Peptide-based PROTACs contain three essential components: a binding motif for the target protein, a short amino acid sequence recognized by an E3 ligase called a degron, and a cell penetrating peptide to facilitate uptake into intact cells. While peptide-based PROTACs have been shown to successfully degrade numerous targets, they have often been found to exhibit low cell permeability and high protease susceptibility.

CPProtectides: Rapid uptake of well-folded β-hairpin peptides with enhanced resistance to intracellular degradation.

Cell penetrating peptides (CPPs) have emerged as powerful tools for delivering bioactive cargoes, such as biosensors or drugs to intact cells. One limitation of CPPs is their rapid degradation by intracellular proteases. β-hairpin "protectides" have previously been demonstrated to be long-lived under cytosolic conditions due to their secondary structure.