Cell-penetrating peptides (CPPs) are known to internalize exogenous macromolecules and have received much attention for their pharmaceutical potential. The most commonly studied natural and synthetic CPPs include Penetratin, Tat, and (Arg)9; these CPPs are between 9-30 amino acid residues, feature multiple positive charges, and can efficiently internalize cargo without celltype specificity or chiral receptors [1]. Although their secondary structure and amphipathicity varies, it is thought that the presence of multiple positively-charged residues is critical to achieve uptake into the cell [1]. In addition to the presence of positive charges, past research shows that myristoylation of peptides increases their uptake into cells [2]. Our research suggests that pseudopeptides much simpler than the commonly studied CPPs can also efficiently internalize cargo, so long as the critical cationic and lipophilic features are conserved [3]. The solution-phase synthesis of a novel, minimalist CPP which encapsulates these core features is presented here (Figure 1).
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